From the Division of Global HIV/AIDS, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, GA.
Received for publication April 22, 2011; accepted April 28, 2011.
Disclaimer: The findings and conclusions in this editorial are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.
The authors have no funding to disclose.
Correspondence to: Bess Miller, MD, MSc, Division of Global HIV/AIDS, Center for Global Health, Centers for Disease Control and Preventioon, 1600 Clifton Road, N.E., Mailstop E-04, Atlanta, GA 30333 (e-mail: firstname.lastname@example.org).
The articles by Nicholas et al1 and Petit et al2 in this issue of the Journal of Acquired Immune Deficiency Syndromes report on the incidence of tuberculosis (TB) before and after the initiation of highly active antiretroviral therapy in high and low-TB-prevalence settings.
The TB incidence rate reported by Nicholas et al1 was high (13 per 100 person-years) during the first 3 months of antiretroviral therapy (ART) in a multicountry African cohort. Petit et al also found high TB incidence (4 per 1000 person-years) during the first 6 months of ART in a low-TB-prevalence setting cohort in the United States. Multiple studies in countries with a high TB burden have consistently documented high rates of TB during the very early months of ART.3-8 This high TB incidence during the early phase of ART is, at least in part, the result of unmasking of subclinical TB during the initial rapid restoration of immune response.9,10 However, suboptimal TB case finding due to the use of poorly sensitive TB screening and diagnostic tools before the initiation of ART is also a contributory factor for this reported high TB incidence. Nicholas et al used respiratory symptoms lasting for a duration of ≥2 weeks as the sole screening criterion to identify TB suspects. This TB screening approach has been shown to have a low sensitivity and likely to miss a large proportion of prevalent cases at the time of ART initiation.11,12 Many of the cases identified as incident TB cases during the first 3 months of ART could have been identified before the initiation of ART with the use of a more sensitive TB-screening tool. The World Health Organization (WHO) recommends that people living with HIV (PLHIV) in resource-constrained settings should be actively screened for TB using an evidence-based symptom screening tool (any one of current cough, fever, night sweats, or weight loss) and that the identified TB suspect should be further evaluated.13 In addition to using a less sensitive TB-screening tool, Nicholas et al used sputum smear microscopy and chest radiography for the diagnosis of TB. These diagnostic tests have a low sensitivity to detect culture-positive TB among HIV-infected individuals and might have missed some prevalent TB cases at the initiation of ART.14
A study in South Africa found that when using routine liquid culture to identify persons with active TB before initiating ART, the TB incidence rates after the initiation of ART were 2-fold lower than previously reported and that the rates during the first 3 months of ART were comparable with the rates during months 4-12.15 This study by Lawn et al suggests that approximately half of incident TB cases during the first 3 months of ART under routine program conditions might have been diagnosed before the initiation of ART by using sensitive screening methods and diagnostic tests such as sputum TB culture. Although there are international efforts to scale up culture-based TB diagnosis, the availability of qualified laboratory facilities that can reliably perform this test remains limited.16,17 Moreover, despite the high sensitivity, automated liquid culture takes a median of >3 weeks to yield a positive result, delaying the diagnosis of TB and thereby limits the value of culture results for clinical management. The new fully automated polymerase chain reaction-based Xpert MTB/RIF assay developed using GeneXpert technology (Cepheid, Sunnyvale, CA) can be used at the district level or even closer to the point of care and can provide TB diagnosis and identify rifampin resistance in <2 hours. This assay has been recently endorsed by the WHO as the first diagnostic test for TB suspects among PLHIV and offers great potential to revolutionize TB diagnosis among this high-risk population.18,19
A low CD4 count was the main risk factor for the development of TB during ART identified in both the articles and highlights the need for the initiation of ART at higher CD4 counts to reduce TB risk. The recently revised WHO guidelines on ART for HIV infection among adults and adolescents recommend the initiation of ART at CD4 count <350 cells per cubic millimeter.20 Although the early initiation of ART in accordance with these new WHO ART guidelines would likely reduce the incidence of TB, the current debate revolves around even earlier initiation of ART to achieve the maximum TB-preventive benefit of ART.21,22 A recent HIV prevention randomised clinical trial (HPTN 052) initiating early ART among serodiscordant couples reported a statistically significant reduction in the risk of extrapulmonary TB (P = 0.0013) among the HIV-infected partner who was starter on ART at a CD4 count of 350-550 cells per cubic millimeter.23 A study from South Africa suggested that minimizing the time spent at CD4 count <500 cells per cubic millimeter as a result of early HIV diagnosis and initiation of ART at higher CD4 counts was necessary to reduce the long-term burden of TB among PLHIV.10 A mathematical modeling study suggests that widespread implementation of ART early in the course of HIV infection using an “HIV test and treat” strategy may have a major impact on controlling HIV-associated TB at a population level.24,25
Nicholas et al found an 88% reduction of TB incidence between the first 3 months of ART and the period after the first year of treatment (13 per 100 vs. 1.5 per 100 person-years.) Similarly, Petit et al also found a dramatic reduction in TB risk between the first 6 months of ART and the period after the first 6 months (4 per 1000 vs. 0.7 per 1000 person-years). A meta-analysis of multiple observational cohort studies in countries with both high and low TB incidence rates reported TB risk reduction of 54-92% during the first few years of ART compared with PLHIV not on ART.26-31
Despite the dramatic reduction in TB risk among PLHIV on long-term ART, this risk remains several times higher than that observed among persons without HIV infection living in the same communities.4,8,10,32 A 5-year follow-up study from South Africa suggested that ART reduced the TB rates from 12.5 per 100 person-years in the first year after the initiation of ART to 2.2 per 100 person-years in the fifth year; however, this later rate was still 3 times higher than that among HIV-seronegative adults in the same community.10 Even among patients who achieved CD4 cell counts >500 cells per cubic millimeter, the TB risk stayed 2 times higher than the background rate. These findings highlight the fact that for long-term reduction of TB among PLHIV on ART, other adjunctive strategies such as isoniazid preventive therapy (IPT) should be implemented along with ART. Several studies have demonstrated the additive benefit of ART and IPT.33-35 A randomized controlled trial conducted in Botswana suggested that tuberculin skin test-positive PLHIV on ART benefited the most from IPT.36 The recent WHO guidelines for intensified TB case finding and IPT for PLHIV in resource-constrained settings recommend that once active TB has been determined to be unlikely (through the application of the same evidence-based symptom screening tool described above), PLHIV should be started on IPT for a minimum of 6 months.13 For longer term protection from IPT, the Guidelines recommend 36 months as a surrogate for life-long IPT. The feasibility and cost effectiveness of life-long IPT, however, needs to be evaluated in programmatic settings.
TB continues to be a major cause of preventable illness and death among PLHIV. Widespread testing for HIV infection and early initiation of ART would substantially reduce the incidence of TB among PLHIV on ART. In addition, aggressive promotion of routine TB symptom screening especially during the early months of ART, use of better diagnostic tools, and implementation of IPT in HIV service settings are needed to effectively control this scourge among PLHIV.
1. Nicholas S, Sabapathy K, Cecilia F, et al. Incidence of tuberculosis in HIV-infected patients before and after starting antiretroviral therapy in 8 sub-Saharan African HIV programs. J Acquir Immune Defic Syndr. 2011;54:311-318.
2. Pettit AC, Jenkins CA, Stinnette SE, et al. Tuberculosis risk before and after highly active antiretroviral therapy initiation: does HAART increase the short-term Tb risk in a low incidence TB setting? J Acquir Immune Defic Syndr. 2011;54:305-310.
3. Moore D, Liechty C, Ekwaru P, et al. Prevalence, incidence and mortality associated with tuberculosis in HIV-infected patients initiating antiretroviral therapy in rural Uganda. AIDS. 2007;21:713-719.
4. 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.
5. Bonnet MM, Pinoges LL, Varaine FF, et al. Tuberculosis after HAART initiation in HIV-positive patients from five countries with a high tuberculosis burden. AIDS. 2006;20:1275-1279.
6. Brinkhof MW, Egger M, Boulle A, et al. Tuberculosis after initiation of antiretroviral therapy in low-income and high-income countries. Clin Infect Dis. 2007;45:1518-1521.
7. Dembele M, Saleri N, Carvalho AC, et al. Incidence of tuberculosis after HAART initiation in a cohort of HIV-positive patients in Burkina Faso. Int J Tuberc Lung Dis. 2010;14:318-323.
8. Rie AV, Westreich D, Sanne I. Tuberculosis in patients receiving antiretroviral treatment: incidence, risk factors, and prevention strategies. J Acquir Immune Defic Syndr. 2011;56:349-355.
9. Lawn SD, Wilkinson RJ, Lipman MC, et al. Immune reconstitution and unmasking of tuberculosis during antiretroviral therapy. Am J Respir Crit Care Med. 2008;177:680-685
10. Lawn SD, Myer L, Edwards D, et al. Short-term and long-term risk of tuberculosis associated with CD4 cell recovery during antiretroviral therapy in South Africa. AIDS. 2009;23:1717-1725.
11. Cain KP, McCarthy KD, Heilig CM, et al. An algorithm for tuberculosis screening and diagnosis in people with HIV. N Engl J Med. 2010;362:707-716.
12. Getahun H, Kittikraisak W, Heilig CM, et al. Development of a standardized screening rule for tuberculosis in people living with HIV in resource-constrained settings: individual participant data meta-analysis of observational studies. PLoS Med. 2011;8:e1000391. doi:10.1371/journal.pmed.1000391.
13. World Health Organization. Guidelines for Intensified Tuberculosis Case-Finding and Isoniazid Preventive Therapy for People Living With HIV in Resource Constrained Settings. Geneva, Switzerland: WHO; 2010.
14. 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;180:903-908.
15. Lawn SD, Kranzer K, Edwards DJ, et al. Tuberculosis during the first year of antiretroviral therapy in a South African cohort using an intensive pretreatment screening strategy. AIDS. 2010;24:1323-1328.
16. WHO. The Global Lab Initiative. Geneva, Switzerland: WHO; 2010.
17. WHO. Expanding and Accelerating Access to Diagnostics for Patients at Risk of Multidrug-Resistant TB. Geneva, Switzerland: WHO; 2010.
18. WHO. Rapid Implementation of the Xpert MTB/RIF Diagnostic Test. Geneva, Switzerland: WHO; 2011.
19. Boehme CC, Nabeta P, Hillemann D, et al. Rapid molecular detection of tuberculosis and rifampin resistance. New Engl J Med. 2010;363:1005-1015.
20. WHO. Antiretroviral Therapy for HIV-Infection in Adults and Adolescents. Geneva, Switzerland: WHO; 2010.
21. Lawn SD, Harries AD, Williams BG, et al. Antiretroviral therapy and the control of HIV-associated tuberculosis. Will ART do it? Int J Tuberc Lung Dis. 2011;15:571-581.
24. Granich RM, Gilks CF, Dye C, et al. Universal voluntary HIV testing with immediate antiretroviral therapy as a strategy for elimination of HIV transmission: a mathematical model. Lancet. 2009:373;48-57.
25. Williams BG, Granich RM, De Cock KM, et al. Antiretroviral therapy for tuberculosis control in nine African countries. Proc Natl Acad Sci USA. 2010;107:19485-19489.
26. Jones JL, Hanson DL, Dworkin MS, et al. HIV-associated tuberculosis in the era of highly active antiretroviral therapy. Int J Tuberc Lung Dis. 2000;4:1026-1031.
27. 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;14:1985-1991.
28. Santoro-Lopes G, de Pinho AM, Harrison LH, et al. Reduced risk of tuberculosis among Brazilian patients with advanced human immunodeficiency virus infection treated with highly active antiretroviral therapy. Clin Infect Dis. 2002;34:543-546.
29. 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.
30. Miranda A, Morgan M, Jamal L, et al. Impact of antiretroviral therapy on the incidence of tuberculosis: the Brazilian experience, 1995-2001. PLoS One. 2007;2:e826.
31. 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;10:489-498.
32. The antiretroviral therapy cohort collaboration. Incidence of tuberculosis among HIV-infected patients receiving active antiretroviral therapy in Europe and North America. Clin Infect Dis. 2005;41:1772-1782.
33. Golub JE, Pronyk P, Mohapi L, et al. Isoniazid preventive therapy, HAART and tuberculosis risk in HIV-infected adults in South Africa: a prospective cohort. AIDS. 2009;23:631-636.
34. Golub JE, Saraceni V, Cavalcante SC, et al. The impact of antiretroviral therapy and isoniazid preventive therapy on tuberculosis incidence in HIV infected patients in Rio de Janeiro, Brazil. AIDS. 2007;21:1441-1448.
35. Innes C. Effectiveness of Isoniazid Preventive Therapy in Reducing Mortality in Patients on ART. 17th Conference on Retroviruses and Opportunistic Infections. San Francisco, CA; 2010.
36. Samandari T, Agizew T, Nyirenda S, et al. 6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial. Lancet. doi:10.1016/S0140-6736(11)60204-3.
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