Patients with HIV-related TB who initiated ART in the first four weeks of tuberculosis treatment had a more than two-fold higher IRIS incidence than patients who initiated ART later. Importantly, IRIS occurring in patients who initiated ART early was more severe, took longer to resolve and required hospitalization more frequently.
Higher IRIS rates in patients starting ART early during tuberculosis treatment have been shown in clinical trials (11
) as well as retrospective and observational studies (1
). In a study conducted in Cambodia, IRIS incidence rates were 3.76 vs 1.53 per 100 person months in the early vs late arms respectively (12
). In another large multi-center trial (AIDS Clinical Trials Group (ACTG) 5221), IRIS rates of 11% with immediate ART vs 5% with early ART were reported (13
), with 11.5% of patients with CD4+ count < 50 vs 5.4% of patients with CD4+ count ≥ 50 developing IRIS. This study also showed a substantial CD4+ count/ART arm interaction, P
= 0.014. Time to IRIS from ART initiation was comparable across the STRIDE and SAPiT studies. The commonest clinical presentation of IRIS in the STRIDE study was lymphadenopathy followed by new onset constitutional symptoms; whereas fever followed by peripheral lymphadenopathy was the commonest clinical presenting features of IRIS in the CAMELIA study. In contrast, new onset or worsening respiratory symptoms then pulmonary infiltrates accounted for the most common presenting IRIS features in the SAPiT trial. These varied presentations of IRIS are likely due to the differing profile of patients in the 3 studies, i.e. patients in the SAPiT trial were all ambulant with smear positive pulmonary tuberculosis, patients in the STRIDE trial were a mix of ambulant and hospitalized patients that had all forms of TB, whereas patients from the CAMELIA trial were largely hospitalized with a clinically significantly lower baseline CD4+ counts than the other 2 trials.
Our study also showed that in severely immunocompromised patients (CD4+ counts <50 cells/mm3
), risk of IRIS was almost 5 times higher in those initiating ART early. It is important to note that within this population, studies have demonstrated substantial decrease in risk of morbidity and mortality with early ART initiation (11
). Patients with CD4+ count ≥50 cells/mm3
did not gain a survival benefit from ART initiation within the first 4 weeks compared to ART initiation at the start of the continuation phase of tuberculosis treatment, but experienced a two-fold (15.3 vs 7.1 per 100 person years) higher risk of developing IRIS (11
). Similarly, no discernable survival or decreased morbidity benefit was evident with early ART initiation in patients with CD4+ counts ≥50 cells/mm3
in the ACTG 5221 study; the incidence rate of AIDS or death was 11.5% in patients who initiated ART within 2 weeks compared to 10.3% in those initiating ART within 8 - 12 weeks of tuberculosis treatment initiation (13
Not only was IRIS more common, it was also more severe in patients initiating ART in the first 4 weeks of tuberculosis treatment. Those who initiated ART early had greater burden of IRIS related morbidity; longer duration of illness, more steroid use, and higher rates of hospitalization. Two-thirds of all severe or life-threatening IRIS associated adverse events occurred in early integrated-treatment arm patients. These patients experienced a disproportionate number of hospitalizations; accounting for approximately 80% of all IRIS-associated hospitalizations in the study. Consistent with previously published data (14
), low baseline CD4+ count and high baseline viral load were significant risk factors for IRIS in our study. Time to IRIS resolution in the early integrated-treatment arm was two-fold higher than the late integrated-treatment arm and three-fold higher than the sequential-treatment arm. Furthermore, 50% of all patients requiring steroids for management of IRIS were in the early integrated-treatment arm. Steroid therapy was prescribed in 10% of IRIS patients in this study to ameliorate the clinical course of IRIS where life-threatening space occupying lesions or danger of respiratory failure existed. The role of corticosteroids in the management of IRIS has however not been clearly defined. On one hand a study has demonstrated that steroids reduced the need for hospitalization and therapeutic procedures, and hastened improvement in IRIS symptoms, while other studies caution steroid use in IRIS as it has been shown to exacerbate underlying opportunistic infections including drug-resistant tuberculosis and Kaposi’s sarcoma (29
). There was no difference in the number of unscheduled medical visits, drug switching from toxicity or virologic failure among patients who developed IRIS compared to patients without IRIS. It is important to underscore that overall we found a relatively low IRIS associated death rate and a relatively benign nature of IRIS. These findings are clinically relevant on two levels; at an individual patient level these findings enhance confidence in co-administering TB and HIV treatment without fear of worsening morbidity and mortality due to IRIS; and, at a public health level these findings indicate that TB and HIV integration can occur without increasing the availability of resources for IRIS management especially in settings where TB and HIV are endemic.
In light of higher IRIS associated morbidity with early ART in tuberculosis treatment, the decision on timing of ART in co-infected patients should be influenced by baseline CD4+ count due to association between risk of IRIS as well as reported morbidity and mortality benefit by CD4+ count strata. Thus, in patients with CD4+ count <50 cells/mm3, balance of benefit/risk would favour initiation of ART within four weeks of TB treatment initiation. On the other hand, in patients with CD4+ counts ≥50 cells/mm3, the decision for early versus later initiation of ART during TB treatment must be weighed against availability of clinical capacity to diagnose and manage IRIS. Hence, careful consideration is required to assess, in each clinical setting, potential benefits versus risks of each strategy. Importantly, in patients with CD4+ count >50 cells/mm3, while ART initiation may be deferred until 8-12 weeks after tuberculosis treatment initiation, every effort should be made to initiate ART no later than 12 weeks after tuberculosis treatment initiation. Additionally, among patients with CD4+ count >50 cells/mm3 with clinical disease of major severity; organ system dysfunction; or low Karnofsky score, Body Mass Index (BMI), haemoglobin or albumin; early initiation of ART should be strongly considered, as these are associated with higher mortality rates.
We acknowledge several limitations to our study. Firstly, as we enrolled ambulant patients with sputum positive pulmonary TB, these results may not be directly generalizable to all forms and severity of tuberculosis in HIV infected patients. Though the differences in patient retention across the 3 study arms was not statistically significant, it is possible but unlikely that there was a greater ascertainment of IRIS in the early integrated-treatment arm compared to the other 2 arms as a result of more patients being retained in that arm.
In the absence of use of placebos in this trial, study clinicians were aware of when a given patient had begun ART, which could have biased the assessment of whether IRIS was present. We mitigated this bias to some extent by the use of standard checklists that were followed for clinical assessments and diagnosis of IRIS. It was not possible to prevent treating clinicians from knowing when patients initiated ART and this may have impacted their patient’s clinical management decision, including hospitalisation. We attempted to minimise this limitation by a standard procedure which required a second opinion on hospitalisation by a separate clinician. Decisions relating to steroid use were made by hospital clinicians unrelated to the study.
Further studies may be necessary to assess IRIS risk in non-ambulant patients and in patients with extra-pulmonary and smear negative pulmonary tuberculosis. While CD4+ count was a strong prognostic indicator of IRIS risk, CD4+ count assays are not always available in many settings. Decisions on timing of ART in individual patients need to be modified by clinical judgement of disease severity; and consideration of capacity to diagnose and manage IRIS. In the absence of a reliable diagnostic test for IRIS, it is possible that misclassification bias occurred. It is likely that milder forms of IRIS was missed, as IRIS diagnosis is dependent on patient self-report for specific symptoms and clinician awareness, especially where diagnostic radiography is not routinely available or inaccessible, even to symptomatic patients. This issue was addressed procedurally through use of a standardized IRIS evaluation checklist which was administered to every patient at each clinical visit. INSHI criteria for IRIS diagnosis was published three years after commencing our study (7
). Despite lack of a standardized case definition for IRIS at the time, we implemented several steps in the design and conduct of the study to ensure consistency in reporting, recording and interpretation of suspected IRIS.
We address an important and current topic in the management of individuals co-infected with HIV and TB, by using data from a randomized clinical trial that had more cases of IRIS (80 patients) than prior reports, and where a single ART regimen was used in a well characterized smear-positive TB cohort. Since integration of tuberculosis and HIV treatment can reduce mortality by 56% (10
), decisions on when to start ART during tuberculosis treatment should take into account the balance of risk and severity of IRIS and potential benefit in relation to morbidity and/or mortality. IRIS is substantially higher in patients starting ART earlier after TB treatment initiation. While patients with severe immunosuppression have a clear survival benefit from early ART initiation despite high IRIS risk (11
) this balance of risks and benefits is different in patients with higher CD4+ counts. Deferring antiretroviral therapy initiation up to 12 weeks after tuberculosis treatment initiation may be an appropriate strategy in stable ambulant patients with CD4+ counts ≥ 50 cells/mm3
as this approach offers lower incidence and less severe IRIS without increasing risk of AIDS or mortality. Future research efforts need to focus on finding a reliable diagnostic marker of IRIS in routine clinical and laboratory settings. Further, a randomized placebo-controlled trial investigating whether the use of corticosteroids in patients with CD4+ counts < 50 cells/mm3
initiating HAART early in TB treatment reduces frequency and severity of IRIS events and need for hospitalization, is warranted. Additionally, validated clinical and laboratory tools to reliably diagnose IRIS will simplify clinical management decisions for TB-HIV co-infected patients.