To the Editors:
New guidelines for the management of latent infection with Mycobacterium tuberculosis (LTBI) have been released by the World Health Organization1 subsequent to the announcement of their novel strategy for the elimination of tuberculosis (TB) in countries of low TB incidence.2 According to this guideline, there is a strong recommendation for high-income countries for systematic testing and treatment of LTBI in people living with HIV, adult and child contacts of pulmonary TB cases, patients initiating tumor necrosis factor antagonist treatment, patients receiving dialysis, patients preparing for organ or hematologic transplantation, and patients with silicosis. Either interferon-γ release assays (IGRAs) or Mantoux tuberculin skin test (TST) should be used to test for LTBI.1,2
Recently, we performed a multinational observational cohort study in Western Europe to evaluate the ability of the TST and the currently available IGRAs (the QuantiFERON-TB Gold in-tube assay and the T-SPOT.TB assay) to predict the progression to TB in patients living with HIV and in other immunocompromised patients in countries of low TB incidence.3 It was found that the frequency of positive test results by TST or IGRAs and the risk for the progression to TB differed among patients from different groups of immunocompromised individuals, and that patients with HIV infection clearly had the highest risk for the development of TB when compared to patients with chronic renal failure, rheumatoid arthritis, solid organ, or stem-cell transplant recipients in the absence of preventive chemotherapy. However, the overall risk of progression to TB in HIV-infected patients in Western-Europe was less than 3.5 per 100 person-years over a 2-year period3 and was thus not substantially higher than in recent contacts of TB patients in Western Europe where the risk for the progression to TB was also found to be very low.4 Physicians in many European countries,5–7 in the United States,8 and in Canada9 are reluctant to strictly test all HIV-infected patients and provide preventive chemotherapy in case of a positive TST or IGRA test result. This emphasizes the need to identify additional risk factors for targeted TB prevention in persons living with HIV in low TB incidence countries.
As ongoing viral replication is a strong risk factor of opportunistic infections in chronic HIV infection,10,11 we reanalyzed the data from our study3 stratified by detection of viral replication in patients with HIV infection. Among 635 patients, 338 (53%) had suppression of viral replication (<50 copies/mL) on antiretroviral therapies at the time of screening for LTBI. Among the remaining 297 patients with detectable HIV load, 114 (38%) were on antiretroviral therapy. Positive TST, enzyme-linked immune-spot assay (ELISPOT) (T-SPOT.TB), and enzyme-linked immunosorbent assay (ELISA) (QuantiFERON-TB Gold in-tube) results were observed in 8.1%, 10.4%, and 8.4%, respectively, of patients with detectable viral replication; these percentages were not significantly different from those of patients with undetectable HIV viral load (5.3%, 9.8%, and 7.7% for TST, ELISPOT, and ELISA, respectively). Within a 2-year follow-up period, none of the patients with viral suppression at the time of LTBI screening developed TB (0/338), regardless of the result of the screening test. In contrast, 6/297 patients with ongoing viral replication developed TB. The incidence of TB in patients with ongoing viral replication was therefore significantly higher compared with patients without viral replication (rate ratio, 13.4; 95% confidence interval: 2.7 to 66.3). The rate of TB in patients with viral replication was between 6.6 and 13.5 times higher for those with a positive LTBI test than for those without a positive LTBI test (Table 1). Comparing patients by antiretroviral therapy status rather than viral suppression did not result in such a clear distinction with regard to risk of TB. Two of the 6 patients who developed TB during follow-up were on antiretroviral therapy at the time of screening. One of these had a positive LTBI test, whereas the other had not. In contrast to the finding of viral suppression, we did not find an association between numbers of circulating CD4+ T cells and the risk for the development of TB in this cohort.3 The study may have been underpowered to show such an association that was observed elsewhere.12
To estimate the effect of different testing and treatment scenarios in patients with HIV, we calculated the numbers needed to treat with preventive chemotherapy to prevent one case of TB based on the absolute risk reduction (1/absolute risk reduction). When targeting preventive chemotherapy to patients with detectable viral replication and a positive immunodiagnostic test, the numbers needed to treat to prevent one case of TB was as low as 8, 13, and 10 with the TST, ELISA, and ELISPOT, respectively. In a public health approach of screening only patients with detectable viral replication, the numbers needed to test and treat when positive to prevent one case of TB was 79, 85, and 59 with the TST, ELISA, and ELISPOT, respectively. This increased number is due to the inability to prevent TB in screen negatives. This approach is more than twice as efficient compared with testing all patients with HIV and treating those positive, where the numbers needed to test and treat if positive would be 166, 199, and 137 with the TST, ELISA, and ELISPOT, respectively. Thus, the presence of viral replication identifies HIV-infected patients at risk for progression to TB substantially better than immunodiagnostic testing alone. It also seems to be superior to the identification by the use of antiretroviral therapy.
Although antiretroviral therapy decreases the risk of TB substantially, this risk still seems to be elevated in HIV-infected individuals as compared to the general population in high TB incidence countries,10,12,13 which may also be due to frequent M. tuberculosis reexposure. It is tempting to speculate that the risk for progression in HIV-infected patients with undetectable viral load in countries of low TB incidence is comparable to the general population because of the absence of continued M. tuberculosis reexposure. Although this study was performed in a large group of patients with HIV infection, it is limited by the low overall number of patients who developed TB. However, if these observations can be confirmed in future studies, they should have implication for management guidelines for patients with HIV infection in countries where the risk for TB is low.
In our study, 71.2% of all patients were on antiretroviral therapy (452/635), and among those, 74.8% had suppressed viral load. This effect of treatment on HIV load is in line with other low incidence regions such as the United States, where more than 75% of HIV-infected patients in care have sustained undetectable viral replication on antiretroviral therapy.14 Patients with viral suppression due to antiretroviral therapy have a very low likelihood of developing active TB disease even if LTBI is present and therefore may be able to forgo screening. Although the percentage of patients with viral suppression and hence the reduction in those requiring screening largely depend on antiretroviral therapy, our data suggest that it would be reasonable to focus LTBI screening on patients with detectable viral replication regardless of the use of antiretroviral therapy, providing that no other risk factors for TB are present. Such a strategy will identify HIV-infected patients with the highest risk of progression to TB and might be cost effective in low TB incidence countries where HIV load testing is routinely performed. Moreover, this may substantially increase physicians' acceptance for targeted LTBI testing and providing preventive chemotherapy in countries where this is not the case at present.
The authors would like to thank the members of the TBnet study team for their joint effort in this study: Judith Bruchfeld MD PhD, Inger Julander MD PhD, Infectious Diseases Unit, Department of Medicine, Karolinska Institute Solna and, Karolinska University Hospital, Stockholm, Sweden; Dragos Bumbacea MD PhD, Department of Pneumology, Elias Emergency University Hospital & Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; Daniela M. Cirillo MD PhD, Emerging Bacterial Pathogens Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy; Asli Gorek Dilektasli MD, Fusun Oner Eyuboglu MD, Division of Pulmonary Diseases, Baskent University School of Medicine, Ankara, Turkey; José Domínguez PhD, Irene Latorre PhD, Servei de Microbiologia, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Ciber Enfermedades Respiratorias, Instituto de Salud Carlos III, Badalona, Spain; Raquel Duarte MD PhD, Departmento de Epidemiologia Clinica, Medicina Preventiva e Saúde Pública Faculdade de Medicina da Universidade do Porto, Porto, Portugal; Martin Ernst PhD, Clinical Infectious Diseases, Research Center Borstel, German Center for Infection Research (DZIF), Tuberculosis unit, Borstel, Germany; Irini Gerogianni MD PhD, Respiratory Medicine, University of Thessaly, Thessaly, Greece; Enrico Girardi MD, Delia Goletti MD PhD, National Institute for Infectious Diseases L. Spallanzani, Rome, Italy; Jean-Paul Janssens MD, Paola M. Soccal, Division of Pulmonary Diseases, Department of Medical Specialties, Geneva University Hospitals, Geneva, Switzerland; Berit Lange MD, Marina Straub MD, Dirk Wagner MD, Department of Infectious Diseases & Center for Chronic Immunodeficiency, Medical Center, University of Freiburg, Freiburg, Germany; Monica Losi PhD, University of Modena & Reggio Emilia, Modena, Italy; Roumiana Markova MD PhD, National Center of Infectious and Parasitic Diseases, Sofia, Bulgaria; Alberto Matteelli MD, Institute of Infectious and Tropical Diseases, WHO Collaborating Centre for TB/HIV co-infection, University of Brescia, Brescia, Italy; Heather Milburn MD, Department of Respiratory Medicine, Guy's & St Thomas' Hospital; King's College, University of London, London, UK; Pernille Ravn PhD, Department for Pulmonary and Infectious diseases, North Zealand Hospital Hillerød, Hillerød, Denmark; Theresia Scholman MD, Department of Transplant and Infection Immunology, Saarland University, Homburg, Germany; Timo Wolf MD, HIV Center, Department of Infectious Diseases, Johann-Wolfgang-Goethe University, Frankfurt, Germany; Aslihan Yalcin MD, Department of Chest Diseases and Tuberculosis, Ankara University, Ankara, Turkey.
1. World Health Organisation. Guidelines on the Management of Latent Tuberculosis Infection, the End TB Strategy. Geneva, Switzerland; 2014.
2. World Health Organization. Towards Tuberculosis Elimination: An Action Framework for Low-incidence Countries. Geneva, Switzerland; WHO: 2014.
3. Sester M, van Leth F, Bruchfeld J, et al.. Risk assessment of tuberculosis in immunocompromised patients. A TBNET study. Am J Respir Crit Care Med. 2014;190:1168–1176.
4. Zellweger JP, Sotgiu G, Block M, et al.. Risk assessment of tuberculosis in contacts by IFN-gamma release assays. A Tuberculosis Network European Trials Group study. Am J Respir Crit Care Med. 2015;191:1176–1184.
5. Gutsfeld C, Olaru ID, Vollrath O, et al.. Attitudes about tuberculosis prevention in the elimination Phase: a Survey among physicians in Germany. PLoS One. 2014;9:e112681.
6. Elzi L, Schlegel M, Weber R, et al.. Reducing tuberculosis incidence by tuberculin skin testing, preventive treatment, and antiretroviral therapy in an area of low tuberculosis transmission. Clin Infect Dis. 2007;44:94–102.
7. Wyndham-Thomas C, Schepers K, Dirix V, et al.. Implementation of latent tuberculosis screening in HIV care centres: evaluation in a low tuberculosis incidence setting. Epidemiol Infect. 2015;1–9. doi:10.1017/S0950268815001594.
8. Lee LM, Lobato MN, Buskin SE, et al.. Low adherence to guidelines for preventing TB among persons with newly diagnosed HIV infection, United States. Int J Tuberc Lung Dis. 2006;10:209–214.
9. Brassard P, Hottes TS, Lalonde RG, et al.. Tuberculosis screening and active tuberculosis among HIV-infected persons in a Canadian tertiary care centre. Can J Infect Dis Med Microbiol. 2009;20:51–57.
10. Lawn SD, Bekker LG, Wood R. How effectively does HAART restore immune responses to Mycobacterium tuberculosis? Implications for tuberculosis control. AIDS. 2005;19:1113–1124.
11. 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;19:2109–2116.
12. Badri M, Wilson D, Wood R. Effect of highly active antiretroviral therapy on incidence of tuberculosis in South Africa: a cohort study. Lancet. 2002;359:2059–2064.
13. 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.
14. Centers for Disease Control and Prevention (CDC). Vital signs: HIV prevention through care and treatment–United States, MMWR Morb Mortal Wkly Rep. 2011;60:1618–1623.