Tuberculin skin testing and isoniazid preventive therapy
Of the 11 026 patients, 5492 (49.8%) received at least one TST, of whom 1363 (24.8%) had a positive result. IPT was started in 815 of tuberculin-positive patients (59.8%), and 6 months of treatment was completed in 631 of those starting (77.4%), or 46% of those who were TST positive. Among the 4129 patients who were TST negative, 190 (4.6%) began IPT and 143 (75.3%) completed at least 6 months. An additional 91 HIV-infected patients who had no record of receiving a TST began IPT, and 60 (65.9%) completed at least 6 months. In total, 1096 patients (10%) started IPT and 834 (76.1%) completed 6 months.
Tuberculosis during follow-up
During the 2-year follow-up period, 391 individuals were diagnosed with tuberculosis [incidence rate 2.28 cases per 100 person-years (PY), 95% confidence interval (CI) 2.06–2.52]. Compared with those who did not have tuberculosis during the 2-year period, patients with an episode of tuberculosis were younger (mean age 36.3 versus 38.7 years; P < 0.01), had a lower median baseline CD4 cell count (172 versus 369; P < 0.01) and a mean viral load one log10 greater (4.09 versus 3.45; P < 0.01). There were 15 cases (1.4%) of tuberculosis diagnosed among the 1096 who started IPT compared with 376 cases out of 9930 (3.8%) among those who did not receive IPT (P < 0.01). Among patients with a positive TST, 13 tuberculosis cases were diagnosed among 815 patients starting IPT (1.6%) versus 63 of 548 patients not starting treatment (11.5%; P < 0.01).
ART was received by 8128 patients (73.7%) at some point before the end of follow-up, of whom 6142 (75.6%) began on or before 1 September 2003, and the remaining 1986 began ART after 1 September 2003. A total of 231 tuberculosis cases were diagnosed among the 8128 patients receiving ART (2.8%) compared with 160 cases among those who never received ART (5.5%; P < 0.01). Of the 231 tuberculosis cases among ART users, 76 (32.9%) were diagnosed with tuberculosis within 6 months of beginning ART.
The median CD4 cell count was 213 cells/μl (IQR 114–330) at the start of ART and 365 cells/μl (IQR 224–564) at the start of IPT. Of 4506 patients with a CD4 cell count of less than 350 cells/μl at the start of follow-up, 223 (4.9%) developed tuberculosis compared with 68 patients (1.4%) with higher baseline CD4 cell counts (P < 0.01). Of 1554 patients with no CD4 cell data, 100 (6.4%) developed tuberculosis. Among 291 tuberculosis cases with CD4 cell data, 223 (76.6%) were among those with CD4 cell counts of less than 350 cells/μl.
Tuberculosis incidence rates were calculated using PY of follow-up as the denominator for the entire cohort and among the four primary exposure groups (Table 2). The overall tuberculosis incidence in the cohort was 2.28 cases per 100 PY (95% CI 2.06–2.52). Patients who did not receive ART or IPT had a tuberculosis incidence of 4.01 episodes/100 PY (95% CI 3.40–4.69); those who received only ART had a rate of 1.90/100 PY (95% CI 1.66–2.17); those who received only IPT had a rate of 1.27/100 PY (95% CI 0.41–2.95); and those who received both ART and IPT had a rate of 0.80/100 PY (95% CI 0.38–1.47).
Proportional hazards analyses
Unadjusted proportional hazards analysis revealed that both ART [relative hazard (RH) 0.55; P < 0.01] and IPT (RH 0.36; P < 0.01) were independently associated with a decreased risk of tuberculosis compared with no treatment (Table 3). Patients receiving both IPT and ART were even less likely to develop tuberculosis than those who received no treatment or either treatment alone (RH 0.23; P < 0.01).
Compared with patients less than 30 years old, patients 40–49 years of age had a decreased risk of tuberculosis (RH 0.61; P < 0.01) as did those aged 50 years or older (RH 0.42; P < 0.01). Sex was not associated with the incidence of tuberculosis (RH 0.89; P = 0.31). Using a baseline CD4 lymphocyte count of less than 200 cells/μl as the reference group, a CD4 lymphocyte count between 200 and 349 cells/μl was associated with a 65% decreased risk of tuberculosis (RH 0.34; P < 0.001); CD4 cell counts between 350 and 499 cells/μl were associated with a 78% deceased risk of tuberculosis (RH 0.22; P < 0.001); and CD4 cell counts greater than 500 cells/μl were associated with an 87% reduction in risk (RH 0.13; P < 0.001). A baseline viral load of 10 000–99 999 copies/ml (RH 1.39; P = 0.04) and 100 000 copies/ml or greater (RH 4.27; P < 0.001) was significantly associated with an increased risk of tuberculosis when compared with patients with viral loads of less than 10 000 copies/ml.
In an adjusted proportional hazards analysis, ART alone was significantly associated with a reduced risk of tuberculosis (aRH 0.41; P ( 0.001) whereas IPT was no longer significant (aRH 0.57; P = 0.34; Table 3). The use of both IPT and ART was associated with a 76% lower risk of tuberculosis compared with no treatment (aRH 0.24; P < 0.001). The adjusted model revealed similar estimates for the association between CD4 cell counts and age with tuberculosis incidence.
Separate proportional hazards models were generated according to baseline CD4 cell counts (< or ≥ 350 cells/μl; Table 4). For patients with CD4 cell counts less than 350 cells/μl, the protective effects of ART alone (aRH 0.46; P < 0.001) were greater than IPT alone (aRH 0.88; P = 0.86) when compared with no treatment. When both ART and IPT were taken, however, there was a 72% decrease in tuberculosis risk (aRH 0.28; P < 0.001). There was a trend towards decreasing tuberculosis risk among older patients.
Among patients whose baseline CD4 cell counts were greater than 350 cells/μl, the protective effects of ART (aRH 0.39; P < 0.001) were again greater than IPT (aRH 0.26; P = 0.18) when compared with no treatment. When both were given, a 78% reduction in risk was observed (aRH 0.22; P = 0.04). In this CD4 cell stratum, a previous tuberculosis diagnosis increased the risk of tuberculosis twofold (aRH 2.27; P < 0.01). The trend in decreasing tuberculosis risk among older patients was not evident in this stratum.
Our study confirms that tuberculosis is a common HIV-related complication in this population with high levels of ART, with an incidence of 2.28 cases per 100 PY, more than 20-fold higher than for the general population of Brazil . In univariate analyses of tuberculosis incidence rates, the use of ART, IPT or the combination of both ART and IPT was associated with substantially lower risks. Multivariate analyses confirmed that ART was independently associated with a 59% reduction in tuberculosis incidence, whereas the use of both IPT and ART further reduced the incidence to approximately 24% of the rate of treatment-naive patients. These results suggest that the provision of antiretroviral drugs and tuberculosis preventive therapy could have a more substantial impact on HIV-related tuberculosis than either strategy alone over a minimum of 2 years of follow-up.
The combination of IPT and ART was associated with significant reductions in tuberculosis for patients with both advanced HIV disease and among patients with earlier HIV disease. In the population of patients with more advanced HIV disease (CD4 cell counts < 350 cells/μl), over a period of 2 years, ART alone was associated with a significantly reduced tuberculosis incidence, whereas IPT alone was not. In patients with CD4 cell counts greater than 350 cells/μl at baseline, ART significantly reduced tuberculosis risk, IPT reduced the risk but not at a statistically significant level, whereas the combination reduced the risk substantially.
We also found that a previous diagnosis of tuberculosis was associated with a risk of tuberculosis during follow-up for patients with higher CD4 cell counts. HIV infection increases the risk of recurrent tuberculosis as a result of re-infection or relapse by nearly 19-fold [28,29]. Two previous studies have found the recurrence of tuberculosis to be associated with lower CD4 cell counts [30,31]; our analysis found that previous tuberculosis was a significant risk factor for incident tuberculosis in patients with higher CD4 cell counts. This discrepancy could be caused by differences in tuberculosis treatment in Brazil, where higher rates of interruption are noted. Secondary isoniazid prophylaxis has been an effective method of preventing tuberculosis recurrence among HIV-infected patients, although this is not practised in most of the world [32,33]. Our results suggest that patients with previous tuberculosis are at an increased risk of another tuberculosis diagnosis, thus the use of secondary isoniazid prophylaxis in this population should be considered seriously.
Increasing age was associated with a decreased risk of tuberculosis, although the association was considerably stronger in patients with lower baseline CD4 cell counts. This observation is somewhat perplexing, as older age is usually associated with a higher risk of tuberculosis infection and disease. We found an interaction with older age, lower CD4 cell counts and a history of previous tuberculosis, but cannot explain the lower risk of incident tuberculosis with increasing age in this analysis.
It should be noted that we conducted an intention-to-treat analysis, thereby considering all patients who began IPT equally, regardless of their completion status. When we restricted the IPT group to only those patients who completed 6 months of IPT, the incidence rate decreased further, from 1.27/100 PY for all patients starting IPT to 0.62/100 PY for those completing IPT, whereas the final Cox models remained similar but with an even stronger reduction in tuberculosis risk when both ART and IPT were taken.
There are several limitations to our analysis, which was observational and retrospective. First, our data were abstracted from medical records, not were prospectively collected, and may suffer from missing information. Records in Rio de Janeiro are not maintained in a standardized fashion and therefore clinical monitoring may not have been conducted uniformly in all study clinics. The data abstraction and collection process was, however, closely monitored by trained supervisors, and extensive quality assurance measures were employed. A second limitation is the potential bias by indication that may have been present in our population. We do not know why some patients underwent TST and why some patients began IPT or ART whereas others did not. The use of antiretroviral drugs generally follows national guidelines, and treatment eligibility is monitored by a central drug distribution programme. Nonetheless, the use of tuberculin testing and IPT is also recommended by national guidelines but is not universally adhered to. Whereas the high proportion of patients receiving TST was higher than anticipated (50%), many patients remained untested. A third limitation is that we studied individuals attending HIV outpatient clinics, and did not include those with undiagnosed HIV infection who may have an increased risk of tuberculosis; thus, we could have underestimated the overall risk of tuberculosis. Adjustment for baseline viral load and CD4 cell count, however, should aid in interpretation. Fourth, the limited number of individuals initiating IPT rendered imprecise the estimates of its effects on tuberculosis incidence. Finally, it should be noted that this was a prevalent cohort, probably with some underrepresentation of patients whose HIV disease progressed rapidly, and thus died before the study start date.
A number of randomized clinical trials have demonstrated that IPT can reduce tuberculosis incidence in HIV-infected patients, and guidelines for the management of HIV-infected patients in many countries endorse the use of IPT, but the uptake of this intervention has been limited. Concerns about the ability to rule out active tuberculosis before starting preventive therapy, adherence with treatment, drug toxicity, and the development of isoniazid resistance have all contributed to low enthusiasm for IPT. Several studies have shown, however, that active tuberculosis can be excluded using relatively simple screening measures [34,35], and there is little evidence that IPT results in the emergence of drug resistance . Although there has been a great and understandable interest in expanding the use of ART, which clearly has benefits beyond the prevention of tuberculosis, IPT has been relatively ignored. Our data indicate that the combined effect of IPT and ART may have an even greater impact on tuberculosis incidence than the use of antiretroviral drugs alone.
Implementing a policy of the widespread use of IPT has the potential to reduce the rates of tuberculosis substantially among HIV-infected populations and to reduce the burden of disease in countries affected by dual epidemics of tuberculosis and HIV/AIDS. Isoniazid is extremely inexpensive, easy to administer and generally well tolerated. The broader use of IPT in conjunction with ART is likely to yield important health benefits for individual patients and for communities, and should be a high priority in the scaling up of treatment for HIV infection in the developing world.
The authors thank Rita de Cassia Ferreira, Vitoria Vellozo, and Jacqueline Oliveira from the Municipal Health Secretariat, Rio de Janeiro, and Jeanne Keruly, MSN, of Johns Hopkins University for assistance with this study. We also thank the THRio data abstracting team for their dedication and thorough efforts.
Sponsorship: This work was supported by a Bill and Melinda Gates Foundation grant for the Consortium to Respond Effectively to the AIDS–TB Epidemic (CREATE) and National Institutes of Health grants AI066994 and AI001637.
1. Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, Raviglione MC, Dye C. The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 2003; 163:1009–1021.
2. Corbett EL, Marston B, Churchyard GJ, De Cock KM. Tuberculosis in sub-Saharan Africa: opportunities, challenges, and change in the era of antiretroviral treatment. Lancet 2006; 367:926–937.
3. Reid A, Scano F, Getahun H, Williams B, Dye C, Nunn P, et al
. Towards universal access to HIV prevention, treatment, care, and support: the role of tuberculosis/HIV collaboration. Lancet Infect Dis 2006; 6:483–495.
4. Comstock GW, Ferebee SH, Hammes LM. A controlled trial of community-wide isoniazid prophylaxis in Alaska. Am Rev Respir Dis 1967; 95:935–943.
5. Ferebee SH, Mount FW, Murray FJ, Livesay VT. A controlled trial of isoniazid prophylaxis in mental institutions. Am Rev Respir Dis 1963; 88:161–175.
6. Whalen CC, Johnson JL, Okwera A, Hom DL, Huebner R, Mugyenyi P, et al
. A trial of three regimens to prevent tuberculosis in Ugandan adults infected with the human immunodeficiency virus. Uganda–Case Western Reserve University Research Collaboration. N Engl J Med 1997; 337:801–808.
7. De Pinho AM, Santoro-Lopes G, Harrison LH, Schechter M. Chemoprophylaxis for tuberculosis and survival of HIV-infected patients in Brazil. AIDS 2001; 15:2129–2135.
8. Halsey NA, Coberly JS, Desormeaux J, Losikoff P, Atkinson J, Moulton LH, et al
. Randomised trial of isoniazid versus rifampicin and pyrazinamide for prevention of tuberculosis in HIV-1 infection. Lancet 1998; 351:786–792.
9. Pape JW, Jean SS, Ho JL, Hafner A, Johnson WD Jr. Effect of isoniazid prophylaxis on incidence of active tuberculosis and progression of HIV infection. Lancet 1993; 342:268–272.
10. Mwinga A, Hosp M, Godfrey-Faussett P, Quigley M, Mwaba P, Mugala BN, et al
. Twice weekly tuberculosis preventive therapy in HIV infection in Zambia. AIDS 1998; 12:2447–2457.
11. Gordin FM, Matts JP, Miller C, Brown LS, Hafner R, John SL, et al
. A controlled trial of isoniazid in persons with anergy and human immunodeficiency virus infection who are at high risk for tuberculosis. Terry Beirn Community Programs for Clinical Researcn on AIDS. N Engl J Med 1997; 337:315–320.
12. Johnson JL, Okwera A, Hom DL, Mayanja H, Mutuluuza K, Nsubuga P, et al
. Duration of efficacy of treatment of latent tuberculosis infection in HIV-infected adults. AIDS 2001; 15:2137–2147.
13. Casado JL, Moreno S, Fortum J, Antela A, Quereda C, Navas E, et al
. Risk factors for development of tuberculosis after isoniazid chemoprophylaxis in human immunodeficiency virus-infected patients. Clin Infect Dis 2002; 34:386–389.
14. Quigley MA, Mwinga A, Hosp M, Lisse I, Fuchs D, Porter JDH, et al
. Long-term effect of preventive therapy for tuberculosis in a cohort of HIV-infected Zambian adults. AIDS 2001; 15:215–222.
15. 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.
16. Santoro-Lopes G, de Pinho AM, Harrison LH, Schechter M. 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.
17. Jones JL, Hanson DL, Dworkin MS, DeCock KM. HIV-associated tuberculosis in the era of highly active antiretroviral therapy. The Adult/Adolescent Spectrum of HIV Disease Group. Int J Tuberc Lung Dis 2000; 4:1026–1031.
18. 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.
19. Girardi E, Sabin CA, D'Arminio Monforte A, Hogg B, Phillips AN, Gill MJ, et al
. Incidence of tuberculosis among HIV-infected patients receiving highly active antiretroviral therapy in Europe and North America. Clin Infect Dis 2005; 41:1772–1782.
20. Godfrey-Faussett P. World Health Organization/UNAIDS. Policy statement on preventive therapy against tuberculosis in people living with HIV, Report of a meeting held in Geneva 18–20 February 1998. Geneva, Switzerland, WHO 2003.
21. Getahun H, Van Gorkom J, Harries A, Harrington M, Nunn P, Perriens J, et al
. Interim policy on collaborative TB/HIV activities. Geneva, Switzerland. Stop TB Department and Department of HIV/AIDS. World Health Organization 2004.
22. Okie S. Fighting HIV – lessons from Brazil. N Engl J Med 2006; 354:1977–1981.
24. Moulton L, Golub JE, Durovni B. Statistical design of THRio: a phased implementation clinic-randomized study of a tuberculosis preventive therapy intervention. Clinical Trials: The Journal of the Society for Clinical Trials 2007; 4:190–199.
25. Moore RD. Understanding the clinical and economic outcomes of HIV therapy: the Johns Hopkins HIV clinical practice cohort. J Acquir Immune Defic Syndr 1998; 17(Suppl 1):S38–S41.
26. Castelo Filho A, Kritski AL, Barreto AW, Lemos ACM, Netto AR, Guimaraes CA, et al
. II Brazilian consensus on treatment of tuberculosis – Brazilian guidelines for tuberculosis 2004 [in Portuguese]. J Bras Pneumol 2004; 30(Suppl. 1):S62–S64.
27. World Health Organization. Global tuberculosis control: surveillance, planning, financing. Geneva, Switzerland: World Health Organzation 2006.
28. Sonnenberg P, Murray J, Glynn JR, Shearer S, Kambashi B, Godfrey-Faussett P. HIV-1 and recurrence, relapse, and reinfection of tuberculosis after cure: a cohort study in South African mineworkers. Lancet 2001; 358:1687–1693.
29. Driver CR, Munsiff SS, Li J, Kundamal N, Osahan SS. Relapse in persons treated for drug-susceptible tuberculosis in a population with high coinfection with human immunodeficiency virus in New York City. Clin Infect Dis 2001; 33:1762–1769.
30. Pulido F, Pena JM, Rubio R, Moreno S, Gonzalez J, Guijarro C, et al
. Relapse of tuberculosis after treatment in human immunodeficiency virus-infected patients. Arch Intern Med 1997; 157:227–232.
31. Nettles RE, Mazo D, Alwood K, Gachuhi R, Maltas G, Wendel K, et al
. Risk factors for relapse and acquired rifamycin resistance after directly observed tuberculosis treatment: a comparison by HIV serostatus and rifamycin use. Clin Infect Dis 2004; 38:731–736.
32. Churchyard GJ, Fielding K, Charalambous S, Day JH, Corbett EL, Hayes RJ, et al
. Efficacy of secondary isoniazid preventive therapy among HIV-infected Southern Africans: time to change policy? AIDS 2003; 17:2063–2070.
33. Fitzgerald DW, Desvarieux M, Severe P, Joseph P, Johnson WD Jr, Pape JW. Effect of posttreatment isoniazid on prevention of recurrent tuberculosis in HIV-1-infected individuals: a randomised trial. Lancet 2000; 356:1470–1474.
34. Mosimaneotsile B, Talbot EA, Moeti TL, Hone NM, Moalosi G, Moffat HJ, et al
. Value of chest radiography ina tuberculosis prevention programme for HIV-infected people, Botswana. Lancet 2003; 362:1551–1552.
35. Day JH, Charalambous S, Fielding KL, Hayes RJ, Churchyard GJ, Grant AD. Screening for tuberculosis prior to isoniazid preventive therapy among HIV-infected gold miners in South Africa. Int J Tuberc Lung Dis 2006; 10:523–529.
36. Balcells ME, Thomas SL, Godfrey-Faussett P, Grant AD. Isoniazid preventive therapy and risk for resistant tuberculosis. Emerg Infect Dis 2006; 12:744–751.
Keywords:© 2007 Lippincott Williams & Wilkins, Inc.
antiretroviral therapy; Brazil; HIV; isoniazid; tuberculosis