Naidoo K, Yende-Zuma N, Padayatchi N, Naidoo K, Jithoo N, Nair G, Bamber S Gengiah S, El-Sadr WM, Friedland G, Abdool Karim S. The immune reconstitution inflammatory syndrome after antiretroviral therapy initiation in patients with tuberculosis: Findings from the SAPiT trial. Ann Intern Med. 2012 Sep 4;157(5):313-24.
To assess the impact of two different regimens for initiating antiretroviral therapy (ART) on the incidence, severity, and outcomes of immune reconstitution inflammatory syndrome (IRIS) in patients with HIV-related tuberculosis (TB).
An outpatient clinic in Durban, South Africa.
Open-label randomized controlled trial (RCT).
HIV-infected patients aged ≥18 years with sputum smear-positive TB and a CD4 count of <500/µL.
IRIS incidence, severity and outcomes relevant to each of three treatment groups.
This study is an analysis of IRIS data (by treatment group) in the Starting Antiretroviral Therapy at Three Points in Tuberculosis Patients (SAPiT) trial, which was conducted from June 2005 to July 2010. Patients were randomly assigned to initiate ART within four weeks of TB treatment initiation (early integrated treatment group), within four weeks after completion of the intensive phase of TB treatment (late integrated treatment group), or within four weeks after completion of TB therapy (sequential treatment group). The standard first-line ART regimen comprised twice daily lamivudine (300 mg), twice daily enteric-coated didanosine (250 mg for patients weighing <60 kg or 400 mg for patients weighing >60 kg), and once daily efavirenz (600 mg). Study patients were evaluated for features of suspected IRIS using a standardized set of criteria at every study visit. IRIS was defined as the occurrence of new-onset or worsening symptoms, signs, or radiographic features temporally related to initiation of ART or TB treatment and an increase in CD4 cell count. Confirmed ART or TB treatment failure, toxicity, non-adherence, a new concurrent opportunistic infection (OI) or other complications were excluded before IRIS was diagnosed. The IRIS definition used in this study varied from published case definitions (1, 2) in that it did not require patients to have an initial response to TB treatment or to have the results of tuberculin skin tests convert from positive to negative.
Six hundred forty-two patients were randomized to one of the three treatment groups. The trial's primary analysis (3) found that in the early integrated treatment group, AIDS-free survival increased in patients with CD4 cells <50/µL. In people with CD4 counts ≥50/µL, however, late integrated ART reduced the risks of IRIS and other ART-associated adverse events without increasing the risk of AIDS or death.
In the current analysis, 43/214 (20%) patients In the early integrated treatment group developed IRIS, compared to 18/215 (8.4%) in the late integrated treatment group and 19/213 (9%) in the sequential treatment group. the IRIS incidence rate ratio (IRR) per 100 person-years overall was 19.5 (95% confidence interval [CI] 14.2 to 26.4) in the early integrated treatment group, 7.5 (95% CI 4.5 to 11.9) in the late integrated treatment group, and 8.1 (95% CI 4.9 to 12.6) in the sequential treatment group. Patients with CD4 cells <50/µL had a higher incidence in all treatment groups; 45.5 (95% CI 24.9 to 76.4) in the early integrated treatment group; 9.7 (95% CI 2.6 to 24.8) in the late integrated treatment group; and 19.7 (95% CI 8.5 to 38.8) in the sequential treatment group.
IRIS occurring in patients in the early integrated treatment group was more severe, took longer to resolve, and more often required hospitalization. Patients in the early integrated treatment group had more than twice the IRIS incidence of the late integrated treatment group (IRR 2.6, 95% CI 1.5 to 4.8, p<0.001) or the sequential treatment group (IRR 2.4, 95% CI 1.4 to 4.4, p<0.001). IRIS in the early treatment group was also more severe than in the other groups. Severe or life-threatening IRIS events (Grade 3 or Grade 4) occurred in 15 (35%), 4 (22%), and 3 (16%) of patients with IRIS in the early integrated, late integrated, and sequential treatment groups, respectively. Patients with IRIS in the early integrated treatment group had higher IRIS-related hospitalization rates than in the late integrated or sequential treatment groups (n=18, 42%; n=44, 22%; n=1, 5%), and had a much longer median time to IRIS resolution (median 70.5 days, inter-quartile range [IQR] 42 to 151 days vs. median 34.0 days, IQR 24 to 118 days vs. median 23.5 days, IQR 11.5 to 40.5 days, respectively, p=0.001).
The authors conclude that the decision on the timing of ART in patients with HIV and TB should be influenced by baseline CD4 cell counts because of the association between risk for IRIS and reported morbidity and mortality benefit by CD4 cell count strata. They propose that in patients with a CD4 count <50/µL, ART should be initiated within four weeks of beginning TB treatment. In patients with CD4 ≥50/µL, they suggest that the decision regarding early versus later initiation of ART during TB treatment must be weighed against the availability of clinical capacity to diagnose and manage IRIS. In patients with CD4 ≥50/µL, the authors suggest that while ART initiation may be deferred for 8 to 12 weeks after beginning TB treatment, it should be initiated no later than 12 weeks after beginning TB treatment. They also say that early initiation of ART should be strongly considered among patients with CD4 ≥50/µL who also have a clinical disease of major severity; organ system dysfunction; or low Karnofsky performance score, body mass index, hemoglobin level, or albumin level, because these variables are associated with higher mortality rates.
The overall risk of bias in this study is low. The study statistician generated a random allocation sequence to assign patients to one of the intervention groups. Patients were randomly assigned in a 1:1:1 ratio (with the use of sealed envelopes) to one of three study groups in permuted blocks of 6 or 9, with no stratification. Study clinicians were not blinded to treatment group allocation when they assessed possible IRIS, but the investigators took measures to mitigate possible bias by using standard checklists for clinical assessments and diagnoses, and requiring a second clinical opinion for hospitalizations. Although the numbers were relatively high (23%-29% at 18 months), patients lost to follow-up were accounted for appropriately.(4) The study compares favorably to its protocol.(5) A limitation of the study, noted by the authors, is that because its participants were ambulatory patients with sputum smear-positive TB, the results may not be directly generalizable to all forms and severities of TB in HIV-infected patients.
A systematic review of the incidence of IRIS and resulting mortality for a range of opportunistic infections in patients starting ART found that in 16 studies with 3,459 patients, the pooled summary incidence of IRIS was 5.7 per 100 person years (95% CI 9.7 to 24.5).(6) Meta-regression analyses showed that the risk of IRIS is associated with CD4 cell count, with a high risk in patients with CD4 <50/µL. ART was strongly associated with a reduced incidence of TB across all CD4 count strata. Earlier ART initiation (at CD4 >350/µL) may be a key component of global and national strategies to control HIV-associated TB and other OIs, and with this to reduce the incidence of IRIS.(7)
Clinicians should carefully assess the potential benefits and risks of each strategy, for each individual patient, in each clinical setting. The World Health Organization (WHO) is expected to release new guidelines on ART for patients with TB in 2013.
- Colebunders R, John L, Huyst V, Kambugu A, Scano F, Lynen L. Tuberculosis immune reconstitution inflammatory syndrome in countries with limited resources. Int J Tuberc Lung Dis. 2006;10:946-53.
- Shelburne SA, Montes M, Hamill RJ. Immune reconstitution inflammatory syndrome: more answers, more questions. J Antimicrob Chemother. 2006;57: 167-70.
- Abdool Karim SS, Naidoo K, Grobler A, Padayatchi N, Baxter C, Gray AL, Gengiah T, Gengiah S, Naidoo A, Jithoo N, Nair G, El-Sadr WM, Friedland G, Abdool Karim Q. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med. 2011 Oct 20;365(16):1492-501.
- Supplement to: Abdool Karim SS, Naidoo K, Grobler A, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med 2011;365:1492-501. [accessed 20 September 2012]
- Protocol for: Abdool Karim SS, Naidoo K, Grobler A, et al. Integration of antiretroviral therapy with tuberculosis treatment. N Engl J Med 2011;365:1492-501. [accessed 20 September 2012]
- Müller M, Wandel S, Colebunders R, Attia S, Furrer H, Egger M; IeDEA Southern and Central Africa. Immune reconstitution inflammatory syndrome in patients starting antiretroviral therapy for HIV infection: a systematic review and meta-analysis. Lancet Infect Dis. 2010 Apr;10(4):251-61.
- Suthar AB, Lawn SD, Del Amo J, Getahun H, Dye C, Sculier D, Sterling TR, Chaisson RE, Williams BG, Harries AD, Granich RM. Antiretroviral Therapy for Prevention of Tuberculosis in Adults with HIV: A Systematic Review and Meta-Analysis. PLoS Med. 2012 Jul;9(7):e1001270.