Over the past two decades, potent antiretroviral therapy (ART) has dramatically reduced morbidity, AIDS progression, and mortality in patients with HIV infection . However, some individuals experience clinical deterioration shortly after ART initiation despite virological efficacy. This phenomenon, known as immune reconstitution inflammatory syndrome (IRIS) [2,3], is usually linked with an exaggerated inflammatory response to either a previously diagnosed and treated infection (paradoxical IRIS) or to an unrecognized and untreated infection (unmasking IRIS) [4,5]. IRIS has been reported to occur in up to 30% of patients after ART initiation, usually within the first weeks [6–10]. This syndrome has been associated with: a large number of pathogens, including Cryptococcus neoformans, cytomegalovirus, varicella-zoster virus, hepatitis B and C, JC virus associated progressive multifocal leukoencephalopathy; and noninfectious diseases such as Kaposi's sarcoma, sarcoidosis and autoimmune disease [11–20]. However, Mycobacterium tuberculosis, a major cause of mortality among HIV-infected patients , is the most frequent cause of IRIS [9,22]. In high tuberculosis prevalence settings, paradoxical tuberculosis-associated IRIS (TB-IRIS) is a common complication following ART initiation and is reported to occur in 8–43% of patients [23–26]. Most descriptions of TB-IRIS have been reported from retrospective analyses or case reports, in which it has been commonly linked to extrapulmonary and disseminated tuberculosis, low baseline CD4+ cell count, favorable response to ART, and a short interval between onset of tuberculosis treatment and ART initiation [27,28]. The fear of managing TB-IRIS is a common reason put forward to delay ART initiation once tuberculosis has been diagnosed. However, recent publications have shown that initiating ART early after tuberculosis treatment onset markedly reduces mortality, particularly in patients with severe immunosuppression [29–31].
Here, we report the incidence, clinical features, outcomes, and risk factors of TB-IRIS in HIV-infected adults enrolled in the CAMELIA trial (ANRS 1295/CIPRA KH001 DAIDS-ES 10425) with both newly diagnosed smear-positive tuberculosis and advanced immunodeficiency.
CAMELIA was a randomized trial designed to determine the optimal timing of ART initiation after tuberculosis treatment onset in Cambodia. From January 2006 to May 2009, we enrolled 661 HIV-infected ART-naive adults with a positive smear for acid-fast bacilli and CD4+ cell count less than or equal to 200 cells/μl, as described elsewhere . Following initiation of a standard 6-month tuberculosis treatment, patients were randomly assigned to initiate ART at either 2 weeks (early-ART group) or 8 weeks (late-ART group) with a combination of stavudine, lamivudine, and efavirenz. Randomization was stratified according to study site and CD4+ cell count at enrollment (≤50 or 51–200 cells/μl). The trial demonstrated that early initiation of ART significantly reduced the risk of mortality by 34% as compared to a later initiation (P <0.006) . Patients included in the current analysis are those with both documented tuberculosis (defined here as a positive culture for M. tuberculosis or positive smear without evidence of nontuberculous mycobacteria in culture), and at least one follow-up visit after having initiated ART.
Tuberculosis-associated immune reconstitution inflammatory syndrome case definition
Characterization of TB-IRIS was a secondary objective of the CAMELIA trial. TB-IRIS was defined as unexplained worsening or emergence of symptoms or signs of tuberculosis (e.g. fever, cough, shortness of breath, lymph node, or exacerbation of disease at other extrapulmonary sites) occurring after ART initiation, in agreement with previously published definitions [2,3,27,32,33]. Differential diagnoses such as poor adherence, drug-related side-effects, and other associated diseases were systematically considered and excluded. Each case of suspected TB-IRIS reported by on-site treating physicians was subsequently validated by at least two experienced physicians, who were members of the study team not involved in the day-to-day management of the patients. The validation process was not blinded and reviewers had full access to medical record documents and outcomes.
The trial was approved by the National Ethics Committee for Health Research of the Cambodian Ministry of Health, the Ethical Review Board of Médecins sans Frontières, and the Institutional Review Board of Immune Disease Institute (Boston, Massachusetts, USA), and conducted according to the principles expressed in the Declaration of Helsinki. All patients enrolled in the study gave written, informed consent to participate. All patient information was entered into a database using coded identification numbers. No information that could reveal patient identity was entered into the database.
Baseline characteristics were compared between patients who did and who did not experience TB-IRIS using χ2 test for categorical variables or Student's t-test for continuous variables. Delay to TB-IRIS was described using Kaplan–Meier estimates. Factors associated with occurrence of TB-IRIS were identified using Cox proportional hazard model. The proportional hazards assumption was checked with the use of a test based on Schoenfeld residuals and was found to be valid for all factors investigated. All factors associated with occurrence of TB-IRIS in univariate analysis with a P value less than 0.20 were entered in the multivariate model, and a backward stepwise procedure was used to identify factors that remained significant. A sensitivity analysis was conducted considering only patients with culture-confirmed and drug-sensitive M. tuberculosis strains. We investigated the association between occurrence of TB-IRIS and mortality using a Cox proportional hazard model, occurrence of TB-IRIS being considered as a time-dependent cofactor. Again, a test based on Schoenfeld residuals was used to check that the proportional hazard assumption was valid. Statistical analyses were performed using STATA 11 (Stata Corp. College Station, Texas, USA). The CAMELIA trial is registered with ClinicalTrials.gov, number NCT00226434.
Among the 661 patients enrolled in the CAMELIA trial, 597 individuals (308 in the early-ART group and 289 in the late-ART group) were considered in this analysis. The remaining 64 patients were excluded for the following reasons: 16 patients were infected with nontuberculous mycobacteria as identified by culture, 37 died, and two withdrew before ART initiation, whereas nine did not have a follow-up visit after ART initiation. As shown in Table 1, male patients represented nearly two-thirds of the study population. The majority of tuberculosis cases were pulmonary tuberculosis (69.7%), with 12.7% of extrapulmonary tuberculosis and 17.6% disseminated tuberculosis. Tuberculosis was confirmed by culture in 88.8% of cases. At ART initiation, mean age was 36 years [standard deviation (SD): 7.9], median CD4+ cell count was 26 cells/μl [interquartile range (IQR): 12–62], and median plasma HIV RNA concentration was 5.6 log10 copies/ml (IQR: 5.2–6.0). Furthermore, patients from the early-ART group had lower hemoglobin level (P <0.001), Karnofsky score (P <0.001), and BMI (P <0.001) and higher alanine aminotransferase level (P = 0.021) than patients from the late-ART group (Table 1).
Incidence and time of occurrence of tuberculosis-associated immune reconstitution inflammatory syndrome
Among the 597 patients included in this analysis who were followed for a median time of 26 months (IQR: 15–36), 155 (26%) experienced TB-IRIS. In the early-ART group, 110 of 308 (36%) patients experienced TB-IRIS as compared with 45 of 289 (16%) in the late-ART group (P <0.001). The overall TB-IRIS incidence rate was 37.9 cases per 100 person-years [95% confidence interval (CI) 32.4–44.4]. As shown by the Kaplan–Meier estimate (Fig. 1), occurrence of TB-IRIS was significantly higher in the early-ART group than in the late-ART group with incidences of 58.2 cases per 100 person-years (95% CI 48.3–70.2) and 20.4 cases per 100 person-years (95% CI 15.3–27.4), respectively (P <0.001).
The median time between ART initiation and TB-IRIS was 14 days (IQR: 10–42) and did not differ between patients enrolled in the early and late-ART groups (P = 0.53). In the majority of patients (143/155), TB-IRIS occurred during the first 3 months of ART. Only 11 patients experienced TB-IRIS between 3 and 6 months after ART initiation (nine in the early-ART group and two in the late-ART group) and one after 6 months. Interestingly, this later patient was lost to follow-up, stopped ART for several months, and developed TB-IRIS within the first month of ART reintroduction.
Clinical and radiological features of tuberculosis-associated immune reconstitution inflammatory syndrome
The most frequent clinical manifestations of TB-IRIS were emergence or worsening of lymphadenopathy (120 patients), and fever (106 patients; Table 2). Abdominal manifestations were also common, including abdominal pain (44 patients), hepatomegaly (16 patients), and ascites (15 patients). Neurological manifestations were observed in eight patients. At the time of TB-IRIS, a chest radiograph was performed in 103 patients. New or worsening chest radiograph abnormalities were observed in 55 patients, the most common being parenchymal opacities (36 patients), mediastinal lymph node enlargement (27 patients), and pleural effusion (17 patients). There were no differences in clinical symptoms of TB-IRIS between patients in the early and late-ART group, with the exception of more frequent enlargement of mediastinal lymph nodes in the late-ART group (P = 0.016; Table 2).
Tuberculosis-associated immune reconstitution inflammatory syndrome treatment and outcome
The median duration of TB-IRIS symptoms was 7.4 weeks (IQR: 4.0–19.8). Of the 155 TB-IRIS cases, 55 patients (35.5%) were treated with NSAIDs for a median time of 12 days (IQR: 9–24) and 59 patients (38%) received steroids for a median time of 40 days (IQR: 24–70; Table 2). Forty-one patients (26.5%) did not receive any anti-inflammatory treatment. Overall, more than 92% (144/155) of patients who presented with TB-IRIS experienced a favorable outcome with regression of symptoms.
Out of 597 patients, 95 (15.9%) died during the overall follow-up. There were 23 deaths among the 155 patients (14.8%) who experienced TB-IRIS and 72 deaths among the 442 patients (16.3%) who did not experience TB-IRIS throughout the study. In a Cox proportional hazard model, there was no association between occurrence of TB-IRIS and mortality [crude hazard ratio: 0.97 (95% CI: 0.60–1.57); P = 0.91]. Out of the 23 deaths that occurred in the 155 patients who experienced TB-IRIS, 12 were definitively not related to TB-IRIS and occurred several weeks or months after resolution of TB-IRIS (voluntary prolonged interruption of follow-up and ART for four patients, lactic acidosis for four patients, two sepsis, one gastrointestinal hemorrhage, and one hemoptysis). Six deaths were directly attributed to TB-IRIS, all in patients from the early-ART group: two had central neurological disorders (one meningitis and one tuberculoma) and four presented with severe abdominal symptoms related to enlarged inflammatory lymph nodes, ascites, and abscess. The five remaining deaths could not be directly attributed to TB-IRIS: stroke was the cause of death in a 60-year-old man, while acute severe hepatotoxicity and intestinal obstruction were noticed in two patients. Another two patients were found dead at home a few weeks after initial improvement of TB-IRIS and hospital discharge. For these five patients, TB-IRIS might have contributed to the fatal outcome despite not being the direct cause of death.
CD4+ cell count gain and viral load suppression
At ART initiation, CD4+ cell count did not differ between TB-IRIS and non-TB-IRIS patients [median (IQR): 27 (12–52) cells/μl and 25 (12–63) cells/μl, respectively; P = 0.06]. After 6 months of tuberculosis treatment, which corresponded to 24 and 18 weeks of ART in the early-ART and late-ART groups, respectively, the median CD4+ cell count gain was significantly higher in patients who experienced TB-IRIS than in those who did not (P = 0.01; Fig. 2). This difference persisted at one year of follow-up (P = 0.02), but not at later time points measured (up to 48 months). Among patients with TB-IRIS, median CD4+ cell count gain was similar at 6 and 12 months of ART in those who received corticosteroids [120 cells/μl (66–156) and 175 cells/μl (111–222), respectively] and those who did not [123 cells/μl (83–197) and 176 cells/μl (122–258), respectively] (P = 0.30 and P = 0.59, respectively). The proportion of patients with undetectable HIV RNA did not differ between those who experienced TB-IRIS and those who did not at anytime after ART initiation (Fig. 2).
Risk factors of tuberculosis-associated immune reconstitution inflammatory syndrome
In multivariate analysis, factors independently associated with an increased risk of TB-IRIS were early ART initiation (P <0.001), extrapulmonary or disseminated tuberculosis (P <0.001), mediastinal lymphadenopathy on chest radiograph at enrollment (P = 0.004), CD4+ cell count of 100 cells/μl or less (P = 0.048), and HIV RNA more than 6 log10 copies/ml at ART initiation (P = 0.031; Table 3). A sensitivity analysis considering only cases with culture positive and drug-sensitive tuberculosis did not affect these findings (data not shown).
Our study reports the largest published series of TB-IRIS in the context of a randomized clinical trial conducted in severely immunocompromised patients (median CD4+ cell count: 26 cells/μl). The proportion of paradoxical TB-IRIS observed during the CAMELIA trial is among the highest reported. Starting ART early after tuberculosis treatment onset was the strongest risk factor for developing TB-IRIS. CD4+ cell count below or equal to 100 cells/μl, viral load higher than 6 log10 copies/ml, extrapulmonary or disseminated tuberculosis also significantly increased this risk.
The CAMELIA trial design allowed us to demonstrate that the occurrence of TB-IRIS was strongly influenced by the timing of ART initiation in adults with advanced immunodeficiency. In multivariate analysis, enrollment in the early-ART group nearly tripled the risk of developing TB-IRIS. It might be due, at least in part, to a higher residual amount of mycobacterial antigen at the time of early ART initiation. This finding is consistent with data reported from the Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPIT) and AIDS Clinical Trials Group Study A5221 (STRIDE) trials, which enrolled less immunocompromised patients who experienced TB-IRIS less frequently [34,35]. A practical implication of our results is that clinicians and patients should be prepared to face a temporary worsening after starting ART early in patients with tuberculosis.
The frequency of TB-IRIS reported in this study is high, but it is consistent with previous reports [25,36–39]. Reported factors that are often associated with TB-IRIS include extrapulmonary or disseminated tuberculosis (presumably because of a high antigen burden), low CD4+ cell count, and high viral load at ART initiation [24,40,41]. The majority of our patients (87.3%) had a CD4+ cell count below 100 cells/μl, which nearly doubled the risk of developing TB-IRIS when compared with a CD4+ cell count ranging from 100 to 200 cells/μl. Similarly, the risk of developing TB-IRIS was doubled in cases of extrapulmonary or disseminated tuberculosis, or when HIV RNA was above 106 log10 copies/ml. Thus, physicians who initiate ART in adults with both CD4+ cell count below 100 cells/μl and extrapulmonary or disseminated tuberculosis should be particularly vigilant regarding potential TB-IRIS. Moreover, detailed and systematic information about its high frequency and management should be part of pre-ART counseling in such patients, similar to what is currently done for adherence and drug side-effects.
In our study, the time between ART initiation and TB-IRIS occurrence was similar in the early-ART and late-ART groups. More than two-thirds of TB-IRIS (105/155) occurred within the first month of ART and 92% (143/155) occurred during the first 3 months. These data are consistent with the definition published by the International Network for the Study of HIV-associated IRIS while our study was ongoing, and that set a limit of 3 months between the initiation of ART and the onset of TB-IRIS manifestations . However, TB-IRIS cases have been reported to occur later, even beyond 6 months post-ART initiation [6,23,37,40,41]. In our study, 11 patients experienced TB-IRIS after 3 months of ART and none after 6 months. The only ’very late presentation’ occurred 6 weeks after ART reinitiation in a patient who had been lost to the trial for 5 months. On the basis of these findings, we suggest that the timing for consensus definition of TB-IRIS should be extended up to 6 months.
The most common presentation of TB-IRIS in CAMELIA included new-onset or enlarging lymph nodes, fever, and abdominal symptoms (abdominal pain, ascites, and hepatomegaly). Although these symptoms are easy to identify, they are nonspecific and are frequently reported in HIV-infected adults with tuberculosis in resource-limited settings, which underscores the difficulty of ruling out potential competing diagnoses such as the occurrence of another opportunistic infection or the progression of HIV disease. However, we note that neurological TB-IRIS occurred in only eight patients of our series, which is lower than what has been previously reported .
In our study, there was no association between occurrence of TB-IRIS and mortality. TB-IRIS was not a common direct cause of death: six (3.9%) of patients who developed TB-IRIS died without another clear cause of death. Even including the five others in whom TB-IRIS itself might have contributed to a fatal outcome despite not being the direct cause of death, case fatality rate reached 7%, which is relatively low in this very advanced immunosuppressed population. Notwithstanding this, we do note that the six TB-IRIS events that were directly assigned as a direct cause of death all occurred in patients enrolled in the early-ART arm.
We observed a greater CD4+ cell count gain in patients with TB-IRIS compared with those without TB-IRIS at 6 and 12 months of follow-up, consistent with other studies [23,37]. However, CD4+ cell gain was similar in the two groups at the end of follow-up. Of interest, we did not observe a lower reconstitution of CD4+ cell count in patients treated with steroids, unlike what has been reported . Furthermore, we found the same high percentage of patients with undetectable plasma viral load in patients with TB-IRIS compared with those without TB-IRIS during the study duration, up to 90% from the first year.
A potential limitation of our study is that some forms of TB-IRIS may not have been recognized by site clinicians, especially those presentations without fever, lymph node enlargement, or major clinical symptoms. We note that these minor forms of TB-IRIS do not require any specific medical management and spontaneously resolve. Furthermore, although it was clearly stated in the study procedures, chest radiograph was not performed in all suspected cases of TB-IRIS, making it difficult to draw definite conclusions on the proportion of new or worsening radiological abnormalities. However, among the two-thirds of patients who had a chest radiograph at the time of TB-IRIS, 53% presented new or worsening radiological abnormalities, whereas at least 29% of patients with TB-IRIS had no chest radiograph modification between tuberculosis diagnosis and the occurrence of TB-IRIS. Although the absence of worsening or new radiological finding does not rule out the diagnosis of TB-IRIS, our data suggest that this simple and noninvasive examination be performed when an event occurs during the first weeks following ART initiation, given the reported high frequency of new-onset or worsening respiratory symptoms and increased lymphadenopathy in TB-IRIS . Another limitation of our study was the lack of established criteria to initiate NSAID or steroids for TB-IRIS. This could explain the relatively high percentage of patients treated with these drugs as the decision to initiate a specific treatment course was not standardized across study sites and largely depended on the site physician's previous experience, expert opinion, or data from observational studies [43,45]. NSAIDs were largely prescribed by clinicians and steroids were added when the symptoms did not resolve quickly, or were initiated to treat life-threatening manifestations. We note that it remains difficult to provide clear therapeutic recommendations as there are no clinical data about efficacy of NSAID in TB-IRIS while steroids have only been shown to reduce morbidity and hospitalization in a single randomized clinical trial . However, the management of TB-IRIS in our series was generally successful and led to more than 90% of events resolution without any sequelae.
Shortening the delay to initiate ART to 2 weeks after tuberculosis treatment onset in severely immunocompromised HIV-infected adults increased the risk of developing TB-IRIS, especially when tuberculosis was extrapulmonary or disseminated. However, TB-IRIS was clinically manageable and outcome was generally favorable. As initiating ART early at 2 weeks after tuberculosis treatment onset provides a marked survival advantage in severely immunocompromised HIV-infected adults [29–31] and that there is no association between occurrence of TB-IRIS and mortality, healthcare managers should reinforce TB-IRIS training in both HIV and tuberculosis programs to strengthen the recognition of this frequent complication by clinicians. Moreover, pre-ART counseling should include systematic information about TB-IRIS. Finally, our data indicate that TB-IRIS should not be deterrent to initiate ART early in resource limited-settings.
The authors would like to thank all patients who participated in the CAMELIA trial, the health workers of the five hospitals, Cambodian health authorities, particularly the National HIVAIDS (NCHADS) and the National Tuberculosis (CENAT) Programs, Médecins Sans Frontières Belgium, and the Organisation Franco-Cambodgienne de Pneumologie.
D.L. wrote the CAMELIA protocol, implemented the trial, supervised clinical issues, reviewed data, interpreted analyses, edited and approved the report. O.M. implemented the trial, supervised clinical issues, reviewed data, interpreted analyses, and edited the report. Y.M. analyzed data, and edited the report. So.C. enrolled and followed patients, reviewed data, and interpreted analyses concerning TB-IRIS. Sa.C. implemented the trial, supervised clinical issues, and reviewed data. L.B. implemented the CAMELIA trial, supervised clinical research issues, and edited the report. M.F. implemented the trial, enrolled patients, and supervised clinical issues. N.P., C.K., and B.D. enrolled and followed patients. E.N. implemented the trial, supervised biological issues, interpreted analyses, and edited report. T.S. implemented the trial, supervised clinical issues, edited and approved the report. J.F.D. wrote the CAMELIA protocol, edited and approved the report. A.E.G. wrote the CAMELIA protocol, reviewed data, interpreted analyses, edited and approved the report. F.X.B. wrote the CAMELIA protocol, supervised clinical issues, reviewed data, interpreted analyses, edited and approved the report. The first draft of this article was written by D.L. and F.X.B. with assistance from A.E.G. The article was edited by D.L., O.M., Y.M., J.F.D., A.E.G., and F.X.B. The final version of the article was approved by all authors.
The CAMELIA trial was funded by the French National Agency for Research on AIDS and viral hepatitis (ANRS 1295) and the U.S. National Institutes of Health/National Institute of Allergy and Infectious Diseases, Division of AIDS (CIPRA KH001/DAID-ES ID 10425). The funders had no role in the design of the study, data collection and interpretation, decision to publish, and preparation of the article. The corresponding author had full access to all study data and had final responsibility for the decision to submit for publication.
Conflicts of interest
J.F.D. reports serving on the international board for HIV treatment of Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme Chibret, and Gilead. All other authors do not report any conflict of interest.
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