TB IRIS Manifestations and Timing
Of the total 61 TB IRIS cases, 42 (69%) occurred in the earlier ART arm and 19 (31%) in the later ART arm. The majority [93.4% (57/61)] of TB IRIS cases met one or more major TB IRIS criteria, whereas 6.6% (4/61) met only 2 or more minor criteria for TB IRIS (Table 3). The most common manifestations of TB IRIS were new or worsening lymphadenopathy (59.0%) and radiographic features of TB (41.0%), with infrequent serositis (8.2%) and central nervous system manifestations (6.6%). Minor TB IRIS criteria of constitutional (54.1%) and respiratory (34.4%) symptoms were also frequent. The majority of IRIS cases occurred in the first 4 months (Fig. 1) after TB treatment initiation [median 57 days (Q1, Q3 22, 84)] and presented significantly earlier in participants randomized to earlier ART vs. later (median 29 vs. 82 days, P < 0.001) (Table 4). Four TB IRIS cases occurred before ART initiation in the later ART arm; no IRIS cases occurred before ART in the earlier arm. Among those who initiated ART before experiencing TB IRIS, median time to TB IRIS after ART initiation was 16 days (Q1, Q3 10, 49), 18 days with earlier and 15 days with later ART initiation (P = 0.28). TB IRIS symptoms lasted a median of 87 days (Q1, Q3 44, 139) with a nonsignificant difference between earlier and later ART initiation (median 92 vs. 70 days, respectively, P = 0.79).
TB IRIS Management and Severity
More than half of the participants [54.1% (33/61)] with TB IRIS received corticosteroids to manage symptoms, with a median treatment duration of 15 days (Q1, Q3 7, 32). Twenty-one participants (34.4%) with TB IRIS required one or more invasive procedures to aid in diagnosis or to manage complications, such as abscess drainage. These procedures included fine-needle aspiration (10), outpatient abscess drainage (3), surgical abscess drainage (1), lymph node biopsy (5), lumbar puncture (2), thoracentesis (1), liver biopsy (1), and surgical pleural drainage (2). Hospitalization was required in 31.1% (19/61) of participants with TB IRIS; no deaths were attributed to TB IRIS. TB IRIS infrequently led to TB treatment interruption (>7 days) (3/61) or HIV treatment interruption (>3 days) (3/61); 2 participants interrupted both ART and TB treatment. Applying the study-defined TB IRIS severity index, severe TB IRIS requiring hospitalization occurred in 19/61 (31.1%), moderate TB IRIS (steroids and/or invasive procedure) in 25/61 (41.0%), and mild TB IRIS in 17/61 (27.9%) (see Table S1, Supplemental Digital Content,http://links.lww.com/QAI/A478). There was no difference in TB IRIS severity with earlier vs. later ART or with CD4+ <50 vs. ≥50 cells per cubic millimeter (exact ordered Wilcoxon P = 0.84 and 0.17, respectively).
Predictors of TB IRIS
Participants developing TB IRIS had significantly lower baseline CD4+ counts (45 vs. 82 cells/mm3, P < 0.001), higher baseline HIV RNA (5.7 vs. 5.4 log10 copies/mL, P < 0.001), and started ART earlier in relation to TB treatment (12 vs. 24 days, P = 0.028) (Table 1). TB IRIS occurred significantly more frequently in participants with confirmed TB compared with those with only probable TB [47/374 (12.6%) vs. 14/432 (3.2%), P < 0.001]. TB IRIS occurred in 14.9% (33/221) of the participants enrolled from South Africa compared with lower proportions among those from other African countries [1.8% (6/333)], South America [9.9% (16/161)], Asia [3.8% (2/52)], and North America [10.3% (4/39)]. Hispanic ethnicity was significantly associated with a 2-fold higher occurrence of TB IRIS compared with non-Hispanic ethnicity [14.0% (19/136) vs. 6.3% (42/670), P = 0.004].
The time to TB IRIS from TB treatment initiation was significantly shorter for those with baseline CD4+ <50 cells per cubic millimeter compared with other CD4+ categories (P = 0.004, Fig. 1) and for earlier ART compared with later (P = 0.002, see Figure S1, Supplemental Digital Content,http://links.lww.com/QAI/A478). In the stratified multivariate Cox proportional hazards model, earlier ART initiation was significantly associated with a shorter time to TB IRIS compared with later ART initiation. The hazard ratio (HR) of developing TB IRIS was 2.47 [90% confidence interval (CI): 1.56 to 3.91, P = 0.001] for earlier ART vs. later ART, after adjusting for male sex (HR: 1.80, 90% CI: 1.09 to 2.98, P = 0.054), enrollment from South Africa vs. elsewhere (HR: 2.78, 90% CI: 1.79 to 4.32, P < 0.001), baseline HIV RNA (HR: 1.83, 90% CI: 1.24 to 2.71, P = 0.011), baseline body mass index (HR: 1.07, 90% CI: 1.01 to 1.13, P = 0.066), and confirmed vs. probable TB at entry (HR: 3.16, 90% CI: 1.90 to 5.24, P < 0.001). We also considered the competing risks of death and lost to follow-up; the results of the competing risks analysis were not different from the Cox analysis.
In HIV-coinfected patients on TB treatment, TB IRIS occurred in 7.6%, with TB IRIS occurring twice as frequently in those with CD4+ counts <50 cells per cubic millimeter vs. ≥50 and in those starting earlier ART (within 2 weeks after TB treatment initiation) compared with those starting later ART. However, in those with CD4 ≥50, earlier initiation of ART did not increase rate of TB IRIS compared with those starting later, indicating that the increased risk of TB IRIS with earlier ART is concentrated in those with very low CD4+ cell counts of <50 cells per cubic millimeter. TB IRIS was not significantly more severe with earlier ART or in those with CD4+ <50 cells per cubic millimeter. Notably, there were no deaths associated with TB IRIS in this series.
As programs globally implement earlier ART in TB coinfection to reduce AIDS progression and death, increased rates of TB IRIS are an expected consequence. As ART implementation is increasingly task shifted from physicians to nurses and other nonphysician providers in resource-limited settings,12 appropriate training for health-care workers in the recognition and management of TB IRIS will be key, as well as access to experienced clinicians to aid in the management of severe and/or complex cases. Providers need the tools and training necessary to diagnose and manage TB IRIS, which includes access to diagnostic testing to exclude other AIDS-related diagnoses and drug-resistant TB, which can each present similarly to TB IRIS.13 Access to invasive procedures may also be necessary, as one-third of STRIDE participants with TB IRIS underwent procedures ranging from fine-needle aspiration to thoracotomy as part of IRIS diagnosis and/or management. The absolute number of invasive procedures was low (21/806); however, this number does not take into account the procedures performed on those in whom TB IRIS was suspected, but ultimately excluded. Once diagnosed, TB IRIS was addressed in the outpatient setting for the majority of patients (69%), and there were no deaths attributed to TB IRIS, indicating that TB IRIS was generally a manageable condition. However, considerable resources were used during TB IRIS management, with inpatient care used in 31.1% of participants and corticosteroids used in over half, with concomitant monitoring for steroid-related complications. TB IRIS episodes were of moderate (41.0%) or severe (31.1%) intensity in the majority of participants experiencing TB IRIS and lasted a median of nearly 3 months, leading to ongoing clinical resources to monitor and manage patients.
Finally, programs may require the resources and infrastructure to provide closer monitoring during the first 2–3 months of TB and HIV cotreatment, as this is a particularly vulnerable time for treatment-related complications. The risk for TB IRIS was greatest in the first month after ART initiation, with median times to TB IRIS presentation of 18 and 15 days in the earlier and later ART initiation arms, respectively. Further research is needed to define optimal monitoring and management strategies for TB IRIS in resource-constrained settings.
Two randomized trials examining when to initiate ART in HIV–TB coinfection had similar findings to the current study, but with several notable differences. Both the Cambodian-based Cambodian Early versus Late Introduction of Antivirals (CAMELIA)14,15 and South African–based Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPIT)16 studies found a significantly higher rate of TB IRIS with earlier ART (36% vs. 16%, P < 0.001, and 20.1% vs. 8.4%, P < 0.001, respectively). However, both studies had a higher overall TB IRIS rate than the current study (26.0% and 12.5%, respectively). This increased rate is attributable in part to the enrollment requirement for AFB smear-positive specimens, increasing the likelihood of culture-positive TB in the TB suspects; indeed, among STRIDE enrollees, the TB IRIS rate was higher in AFB smear or culture-positive participants (12.6%). CAMELIA's high TB IRIS rate of 25% was also derived from the lower median CD4+ cell count of participants (25 vs. 77 cells/mm3 in STRIDE). It is possible that there were additional factors, including racial differences in the study populations. Of note, STRIDE's TB IRIS rate in South African participants (14.9%) is quite similar to the 14.2% reported in the South African SAPIT study, suggesting that racial background may contribute to TB IRIS, in addition to local provider focus on recognition of TB IRIS and access to radiographic tools for IRIS evaluation. CAMELIA reported 154 TB IRIS cases with 7 (4.5%) deaths attributed to TB IRIS, 6 of which occurred in the earlier arm, and SAPIT reported 2 (2.5%) deaths out of 80 TB IRIS events, both in the earlier ART arm. The mortality benefit of earlier ART initiation in both these studies outweighed the mortality attributed to TB IRIS; however, TB patients with advanced AIDS need to be monitored closely in the first months of ART for complications of TB IRIS, which can be severe and, in rare cases, fatal.
TB IRIS is a well-characterized clinical syndrome8,17; however, diagnosis can be challenging as there is no confirmatory laboratory test, and other AIDS- and TB-related processes need to be excluded. Presence of TB IRIS was determined by study investigator evaluation during required study visits every 4 weeks and any unscheduled visits for toxicity evaluations. It is possible that participants with more advanced immunosuppression and those in the earlier ART arm may have been seen more frequently at unscheduled visits because of AIDS complications or medication toxicity, respectively, and thus assessed more often for TB IRIS creating a diagnostic bias. However, an increase in TB IRIS has consistently been reported in other series in association with earlier ART and low CD4+ cell counts.6,17
TB IRIS was more common in participants with earlier ART initiation and CD4+ cell counts <50 cells per cubic millimeter. Overall, TB IRIS occurrence was infrequent at 7.6%. When TB IRIS occurred, the majority (69%) of cases were mild to moderate in severity; however, 31% were hospitalized with TB IRIS and over half received corticosteroids. As ART is increasingly implemented within 2 weeks after TB treatment initiation to reduce AIDS-related complications and mortality, HIV–TB programs will need the diagnostic capabilities, clinical resources, and provider training necessary to diagnose and manage TB-related IRIS.
The authors thank the study participants, the site principal investigators, and staff for their exceptional efforts to conduct the study, coordinate efforts with the in-country TB control programs, and to help build the capacity of integrated HIV–TB services; the data managers, Carol Suckow, BSN, and Lynne Jones, BS; the clinical trials specialist Evelyn Hogg; the DAIDS protocol pharmacist, Ana Martinez, RPh; the field representative, Janet Nicotera, RN, BSN; the study's laboratory technologist, Patty Anthony, BS, CLS; the laboratory data coordinator, Travis Behm, BS; and the community representative, Martha Tholanah Mensah-King.
1. Abdool Karim SS, Naidoo K, Grobler A, et al.. Timing of initiation of antiretroviral drugs during tuberculosis therapy. N Engl J Med. 2010;362:697–706.
2. Havlir DV, Kendall MA, Ive P, et al.. Timing of antiretroviral therapy for HIV-1 infection and tuberculosis. N Engl J Med. 2011;365:1482–1491.
3. Blanc FX, Sok T, Laureillard D, et al.. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med. 2011;365:1471–1481.
4. Abdool Karim SS, Naidoo K, Grobler A, et al.. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med. 2011;365:1492–1501.
5. Meintjes G, Lawn SD, Scano F, et al.. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis. 2008;8:516–523.
6. Lawn SD, Myer L, Bekker LG, et al.. Tuberculosis-associated immune reconstitution disease: incidence, risk factors and impact in an antiretroviral treatment service in South Africa. AIDS. 2007;21:335–341.
7. Haddow LJ, Moosa MY, Mosam A, et al.. Incidence, clinical spectrum, risk factors and impact of HIV-associated immune reconstitution inflammatory syndrome in South Africa. PLoS One. 2012;7:e40623.
8. Meintjes G, Lawn SD, Scano F, et al.. Tuberculosis-associated immune reconstitution inflammatory syndrome: case definitions for use in resource-limited settings. Lancet Infect Dis. 2008;8:516–523.
9. Kaplan EL, Meier P. Nonparametric estimation of incomplete observations. J Am Stat Assoc. 1958;53:457–481.
10. Cox DR. Regression models and life-tables. J R Stat Soc. 1972;34:187–220.
11. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509.
12. Emdin CA, Millson P. A systematic review evaluating the impact of task shifting on access to antiretroviral therapy in sub-Saharan Africa. Afr Health Sci. 2012;12:318–324.
13. Meintjes G, Rangaka MX, Maartens G, et al.. Novel relationship between tuberculosis immune reconstitution inflammatory syndrome and antitubercular drug resistance. Clin Infect Dis. 2009;48:667–676.
14. Blanc FX, Sok T, Laureillard D, et al.. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med. 2011;365:1471–1481.
15. Laureillard D, Marcy O, Madec Y, et al.. Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome after early initiation of antiretroviral therapy in the camelia randomized. AIDS. 2013;27:2577–2586.
16. Naidoo K, Yende-Zuma N, Padayatchi N, et al.. The immune reconstitution inflammatory syndrome after antiretroviral therapy initiation in patients with tuberculosis: findings from the SAPiT trial. Ann Intern Med. 2012;157:313–324.
17. Meintjes G, Rabie H, Wilkinson RJ, et al.. Tuberculosis-associated immune reconstitution inflammatory syndrome and unmasking of tuberculosis by antiretroviral therapy. Clin Chest Med. 2009;30:797–810.
HIV/AIDS; tuberculosis; immune reconstitution inflammatory syndrome; paradoxical reaction
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