Subclinical tuberculosis at the start of HAART in HIV patients can be unmasked by immune reconstitution inflammatory syndrome (IRIS) . The proportion of tuberculosis manifested by IRIS after HAART has, however, not been established. An understanding of the effect of IRIS on the incidence of tuberculosis during HAART may have significant implications for the control of tuberculosis in HIV patients receiving HAART. We therefore aimed to describe the incidence and clinical features of tuberculosis manifested by IRIS after HAART in an intermediate tuberculosis burden area.
The cohort included all adult HIV patients who started HAART at Seoul National University Hospital between 1998 and 2005. The hospital is a 1600-bed, university-affiliated teaching hospital, and is the largest referral centre for HIV/AIDS in South Korea; a quarter of all HIV patients in South Korea are seen at this hospital. HAART is defined as the use of at least three antiretroviral drugs, including protease inhibitors or non-nucleoside reverse transcriptase inhibitors.
Definite tuberculosis was defined as a clinical illness consistent with tuberculosis accompanied by a culture-positive finding for Mycobacterium tuberculosis. Tuberculosis was considered probable if the histopathology and acid-fast staining results were consistent with tuberculosis, or if the patient had a clinical history consistent with active tuberculosis and symptoms that responded to anti-tuberculosis therapy .
No patients were given a tuberculin skin test, as the assay has poor specificity in our largely bacillus Calmette–Guérin-vaccinated population, and has reduced sensitivity in patients with advanced HIV infection . We included tuberculosis events that were newly manifested after the start of HAART. In patients who already had tuberculosis at the start of HAART, only tuberculosis that developed at sites distinct from those of the initial infections were included.
Tuberculosis that developed after starting HAART was classified as IRIS tuberculosis or non-IRIS tuberculosis. The diagnosis of IRIS was based on the previously published definition . In brief, IRIS tuberculosis was defined as either a first presentation of tuberculosis, or a new manifestation at a different site from that of existing tuberculosis, together with an increased CD4 cell count and a reduced HIV-1 viral load, if measured. Continuous variables were compared using the Mann–Whitney U-test. Statistical analyses were performed using SPSS software (version 12.0; SPSS Inc., Chicago, Illinois, USA).
In 482 HIV patients, the median follow-up duration per person was 2.6 years [interquartile range (IQR) 1.3–4.8]. Ninety per cent of the patients were men, 40% of whom were homosexual. The median age was 38 years (IQR 32–47 years), and 99% of the patients were Korean. Fifty-nine per cent of the patients had a diagnosis of AIDS before HAART. Sixty-six patients (14%) had active tuberculosis before starting HAART; of these, 27 (6%) had experienced active tuberculosis more than a year before beginning HAART and 39 (8%) experienced tuberculosis within a year of beginning HAART.
Twenty-seven tuberculosis events developed during the follow-up period. Of 16 cases diagnosed as definite tuberculosis, four (25%) were classified as IRIS tuberculosis and 12 (75%) as non-IRIS tuberculosis. Of the other 11 cases, diagnosed as probable tuberculosis, five (45%) were classified as IRIS tuberculosis and six (55%) as non-IRIS tuberculosis. Of the 11 tuberculosis events that developed within a year after starting HAART, nine (82%) were classified as IRIS tuberculosis. The incidence rate for IRIS tuberculosis was 0.6 per 100 person-years [95% confidence interval (CI) 0.3–1.2] for the total follow-up period, and 2.1 per 100 person-years (95% CI 0.9–3.9) one year after starting HAART.
In the IRIS tuberculosis group, five patients (56%) had a history of tuberculosis before HAART and four (44%) were under tuberculosis treatment at the start of HAART (Table 1). The median baseline CD4 cell count was 30 cells/μl (IQR 20–80) in the IRIS tuberculosis group, significantly lower than the 230 (IQR 108–290) in the non-IRIS tuberculosis group (P = 0.001). The median time from start of HAART to the diagnosis of tuberculosis was 56 days (IQR 38–169) for IRIS tuberculosis and 699 days (IQR 531–861) for non-IRIS tuberculosis (P < 0.001).
In this study, a significant proportion of the tuberculosis cases that developed soon after starting HAART were manifested by IRIS. Many previous studies demonstrated that the incidence of tuberculosis remarkably increased soon after starting HAART in HIV patients [5–7]. Our findings strongly support the theory that IRIS largely accounts for these increased incidences.
The main focus of previous studies on IRIS-associated tuberculosis was on cases with a diagnosis of tuberculosis that antedated the commencement of HAART . In the present study we did not include the paradoxical aggravation of existing tuberculosis in the IRIS tuberculosis group, because we wanted to evaluate the effect of IRIS on the incidence of tuberculosis in HIV patients receiving HAART.
Few IRIS cases have been reported as the first presentation of tuberculosis . A recent study, however, suggested that IRIS may amplify the presentation of active tuberculosis after HAART . In the present study, 56% of IRIS tuberculosis cases did not have overt tuberculosis at the start of HAART. The low CD4 cell counts and high viral loads at baseline of these cases imply that severe immune dysfunction may prohibit the overt clinical manifestation of subclinical or low grade tuberculosis at the time HAART was started.
This study has some limitations. First, it was performed in a single centre in South Korea, which has an intermediate burden of tuberculosis . Therefore, the incidence and clinical significance of tuberculosis manifested by IRIS in areas with different prevalences of tuberculosis are not known. Tuberculosis manifested by IRIS is, however, expected to be profound in high-burden tuberculosis countries where HAART is to be introduced and used extensively [5,6]. Second, the case definition of probable tuberculosis in this study does not exclude non-tuberculosis mycobacterial infections, which may also be associated with IRIS. Third, we can not exclude a paradoxical reaction of tuberculosis itself in tuberculosis cases manifested by IRIS, because a paradoxical reaction of tuberculosis can hardly be distinguished from IRIS by clinical presentation.
This study suggests that clinicians should be alerted to tuberculosis either initially presented or manifested at different sites from existing tuberculosis by IRIS after HAART in HIV patients.
1. Breen RA, Smith CJ, Cropley I, Johnson MA, Lipman MC. Does immune reconstitution syndrome promote active tuberculosis in patients receiving highly active antiretroviral therapy? AIDS 2005; 19:1201–1206.
2. American Thoracic Society. Diagnostic standards and classification of tuberculosis in adults and children
. Am J Respir Crit Care Med
3. Jasmer RM, Nahid P, Hopewell PC. Clinical practice. Latent tuberculosis infection. N Engl J Med 2002; 347:1860–1866.
4. Shelburne SA III, Hamill RJ, Rodriguez-Barradas MC, Greenberg SB, Atmar RL, Musher DW, et al
. Immune reconstitution inflammatory syndrome: emergence of a unique syndrome during highly active antiretroviral therapy. Medicine (Baltimore) 2002; 81:213–227.
5. Bonnet MM, Pinoges LL, Varaine FF, Oberhauser BB, O'Brien DD, Kebede YY, et al
. Tuberculosis after HAART initiation in HIV-positive patients from five countries with a high tuberculosis burden. AIDS 2006; 20:1275–1279.
6. 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.
7. Girardi E, Sabin CA, d'Arminio MA, 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.
8. Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 2005; 5:361–373.