Corticosteroid therapy improves outcomes in people with TB-IRIS in trial

A four-week course of the anti-inflammatory corticosteroid, prednisone, improves outcomes when given to people who develop tuberculosis (TB)-immune reconstitution inflammatory syndrome (TB-IRIS) after starting antiretroviral therapy (ART) - without causing an excess of steroid side-effects or other infections, according to a randomised placebo-controlled trial conducted in Cape Town, and presented on Monday at the Sixteenth Conference on Retroviruses and Opportunistic Infections in Montreal.

“Prednisone reduced the need for medical interventions (the number of days hospitalised and outpatient procedures) for patients with paradoxical TB-IRIS,” said Dr Graeme Meintjes of the University of Cape Town and GF Jooste Hospital. During the time on prednisone, the benefit was consistent across a range of secondary outcome measures as well, including the overall symptom score, quality-of-life and performance scores, radiology score (such as more rapid improvements on chest X-ray) and C-reactive protein levels (CRP), a marker of inflammation.

"But there is one very important caveat that we would urge clinicians to consider before using corticosteroids for treating TB-IRIS: the critical importance of excluding alternative infections, alternative causes for deterioration and drug-resistant TB," said Dr Meintjes.

Background

IRIS occurs in a proportion of people with HIV who start ART and is generally associated with a flare-up of a previously undiagnosed condition (unmasking) or the paradoxical worsening of a condition already being treated, usually during the first few months on ART. The syndrome is thought to result from inflammation directed at an infection such as TB that is still present at the site of disease - for instance, in the lung or the lymph nodes. That inflammation is driven by the recovering immune system reacting aggressively to the presence of, often small, amounts of antigen from an infectious agent.

In sub-Saharan Africa, about a quarter of co-infected people start ART while still on TB treatment, and TB-IRIS occurs in about 8% to 43% of these patients, according to the literature (see review by Meintjes et al. in Lancet Infectious Diseases, 2008).

“Typically patients are improving on TB treatment after having had a diagnosis of TB, and then start ART,” said Dr Meintjes. IRIS manifests with recurrent symptoms, such as night sweats, the return of cough, and signs of TB such as enlargement of lymph nodes and pulmonary infiltrates on chest X-ray.

Given that this is an inflammatory reaction, many clinicians have used adjunctive therapy with corticosteroids, such as prednisone, which has anti-inflammatory properties — and anecdotal reports have suggested that patients respond symptomatically. But there are potential risks associated with this, especially in advanced HIV infection, since giving immunosuppressive therapy has the potential to cause the development of Kaposi’s sarcoma (KS), or to reactivate herpes virus infections and other infections.

The study

This is the first randomised double-blind placebo-controlled clinical trial to study the safety and effectiveness of using a corticosteroid in TB-IRIS (or in any form of IRIS).

To be enroled in the study, subjects had to meet a clinical case definition for TB-IRIS. Prior to ART, there needed to be: strong evidence for the diagnosis of TB in the patient (with microbiologic, histologic or very strong clinical evidence); a demonstrated initial improvement on TB treatment before starting ART; and TB-drug-susceptibility results (if available) showing that their M. tuberculosis strain was not resistant to rifampicin (the cornerstone of first-line TB drug therapy); patients also had to be receiving TB treatment when ART was initiated. Then, within three months of starting ART, they had to develop new or recurrent (radiologically measurable) TB symptoms, including the presence of one or more of the following:

• Lymph-node enlargement
• Cold abscess
• Serous effusion
• Radiographic pulmonary infiltrate.

“In addition, alternative causes for clinical deterioration needed to be excluded,” said Dr Meintjes.

If the person had a life-threatening form of TB-IRIS (neurological involvement, airway compression and respiratory failure), they were treated by the clinical service with prednisone but excluded from the study. Other exclusion criteria included age under 18 years, pregnancy, prior ART exposure, KS, uncontrolled diabetes mellitus, adrenal failure and previous use of adjunctive corticosteroid therapy for the current TB episode.

People who consented to enrol in the study were randomised to receive either placebo or prednisone prescribed at 1.5 mg/kg/day (2 weeks), then 0.75 mg/kg/day (for the following two weeks). Follow-up assessments were performed at the end of weeks 1, 2, 4, 8 and 12. If patients deteriorated on or after going on to the study drug, they could be switched to open-label prednisone at the physician’s discretion. The primary endpoint was the number of days of hospitalisation plus the number of outpatient therapeutic procedures, such as draining serous effusions, which were each counted as an additional hospital day.

Results

A total of 287 potential participants were screened consecutively for the study between June 2005 and December 2007. Of these people, 110 met the entry criteria and consented to enrol (55 in each arm); of these 70 (64%) were female. The median age was 32. Baseline characteristics were evenly matched across both arms of the study, apart from the duration between TB treatment and ART, which was longer in the prednisone arm.

Six patients defaulted for more than seven days or were lost to follow up (all in the placebo arm, p = 0.01). Three chose to quit the study drug in the placebo arm versus one in the prednisone arm. There were three deaths in the prednisone arm and two in the placebo arm (p = 0.7). After enrolment, ten patients were diagnosed with rifampicin resistance (four vs six in prednisone and placebo arms, p = 0.5).

In an intent-to-treat analysis, there was a significant reduction of the need for medical interventions in patients in the prednisone arm, compared to the placebo arm, with a cumulative primary endpoint of one (interquartile range 0 to 3) median number of hospital days in the prednisone arm vs three (IQR 0 to 9) in the placebo arm (p = 0.046). Cumulatively, there were 282 vs 463 days of hospitalization and 27 vs 31 procedures in the prednisone and placebo arms, respectively.

During the 12 weeks of follow up, 35 patients (20 on placebo and 15 on prednisone) were switched to open-label prednisone (p=0.03). However, 18 out of 20 in the placebo arm switched within the first four weeks because they were deteriorating on the study drug (in their case placebo). By contrast, in the prednisone arm, only five patients switched to open-label prednisone in the first four weeks - most switched afterwards because they had initially improved on the study drug and then had relapsed after completing the four weeks on treatment.

There were also reductions, or significant differences, in a number of secondary outcomes. For instance, a five-point score (which looked at, and graded, changes in different symptoms in each patient) demonstrated significant symptom improvement in prednisone vs placebo arm at week two (p = 0.001) and week four (p=0.03). “More patients in the prednisone arm have significantly better symptom response at weeks two and four; while patients in the placebo arm had symptom deterioration,” said Dr Meintjes.

Likewise, chest X-rays of those with pulmonary infiltrates improved significantly more rapidly; and quality-of-life and performance scores were significantly better at weeks two and four in those on prednisone. CRP measurements improved from a median 104 mg/L at baseline to 34 mg/L by week one in those in the prednisone arm, while CRP improved more slowly in the placebo arm (mostly after the four weeks of study drug).

“On the flipside, the important thing was that there was no excess of adverse events or infections or serious infections in the prednisone arm,” said Dr Meintjes. There was no difference in mortality. During the course of follow up, about 30 patients in both arms had symptoms that might be attributed to corticosteroid side effects (such as hypertension, oedema, hypoglycaemia, hypomonia, acne, gastritis, Cushingold features). But during the first four weeks on study, only eight patients had side-effects in the prednisone arm vs three in the placebo, which did not reach statistical significance (p = 0.11). There were similar numbers of infections in both arms, but severe infections occurred in only two people in the prednisone arm vs four in the placebo arm (p = 0.4). There were no episodes of KS.

Conclusion and implementation in the field

“We would advocate the use of prednisone to treat patients with TB-IRIS,” said Dr Meintjes. It consistently improved outcomes in number of measures in patients with TB IRIS - despite crossovers to open-label prednisone, which may have diminished or dilated the observed effect size. He also stressed that for some patients who relapsed when they went off study drug, four weeks of prednisone may be too short.

But Dr Meintjes reiterated the importance of excluding drug-resistant TB and other clinical conditions.

So in an interview, aidsmap asked Dr Meintjes how actively TB-IRIS is being recognised and managed in resource-limited settings today, as well as the minimum baseline steps that clinicians should take to exclude alternative causes of symptoms before treating a person with prednisone.

He responded that many mild cases, “where it’s just a return of cough, might be missed in a busy clinic, but I don’t think people miss the more severe end of the spectrum, such as when patients have life-threatening or fatal TB-IRIS (like TB-IRIS in their central nervous system). But whether they are always attributed to TB-IRIS is a different question because people might think that it is another opportunistic infection rather than TB-IRIS.”

But the exclusion of other conditions in patients who present with TB-IRIS can be a very difficult clinical situation.

“You’ve got a patient who has advanced HIV infection, often a low CD4 count, who’s on treatment for TB and on a host of drugs for their TB as well as their antiretrovirals and other therapies, and are now clinically deteriorating. And the question is: is that due to TB-IRIS? Is it due to another opportunistic infection? Is it a drug reaction? And because TB-IRIS is a heterogenous condition, the work-up will depend on the manifestations and the site of presentation of the TB-IRIS.”

“If a patient presents with recurrent respiratory symptom, i.e. cough and constitutional symptoms such as night sweats, after starting ART, it could be a bacterial chest infection. So we would often cover the patient with an antibiotic for that before considering steroids, and then do a chest radiograph to look for features of PCP. For other manifestations, such as neurological manifestations, we would want to exclude cryptococcol meningitis. So it very much depends on the presentation,” he said.

Thus, the safe provision of prednisone to people suspected of having TB-IRIS will require a certain level of clinical expertise, diagnostic capacity and a high index of suspicion for the various conditions that may affect people with HIV.