IRIS and risk of early death among HIV+ people with tuberculosis

Gregory Bisson of the University of Pennsylvania and colleagues performed an analysis of a prospective cohort study in Botswana. In a cohort of 170 advanced HIV/TB patients who started ART and TB treatment, screening for inflammatory cytokines showed that pre-ART levels of cytokines such as MCP-I, interleukin 6 (IL-6), and IL-10 were very high in the 18 people who died, whereas pre-ART cytokine levels in the 33 TB-IRIS patients (only 1 of whom died) were very low.

"Pre-ART risk profiling of each outcome is possible and should be investigated in order to direct appropriate interventions to each patient population," said Bisson.

Background

HIV positive people with advanced HIV and TB who have low CD4 T-cell counts are at increased risk for adverse outcomes after ART initiation.

One adverse outcome that has been extensively studied is paradoxical TB-IRIS. This is when a person with a known diagnosis of tuberculosis taking TB treatment is then put on ART and appears to worsen clinically -- in a way that is associated with inflammatory signs and symptoms -- despite having good TB microbiological response and good virological response on treatment. IRIS occurs when the immune system grows stronger due to ART and begins to respond to existing pathogens.

TB-IRIS is associated with significant morbidity and, in rare cases, mortality, and can be difficult to manage particularly in resource-limited settings. It is also something providers will be seeing more of with the new strategy of ART initiation during early TB treatment, as studies have recently shown that TB-IRIS is more common and more severe with earlier ART. What has been less well studied, according to Bisson, is mortality despite a patient starting both TB treatment and ART.

"This is not necessarily uncommon, however -- this occurred in 18% and 7% percent of subjects enrolled in 2 'when to start' [ART in coinfected patients] studies, CAMELIA and ACTG-5221, respectively," said Bisson. "We recently showed in Botswana that patients who died despite initiation of both TB treatment and ART have remarkably diminished cellular immune recovery on ART despite profound virologic response."

Bisson also pointed out that although a number of studies have investigated cytokine profiles and the risk of IRIS, no studies in HIV/TB coinfected patients to date have actually looked at the immunological risk factors for both TB-IRIS and early mortality within the same cohort -- which could be important because ideally providers would want to be able to identify patients at high risk of either outcome prior to ART initiation. Therefore, his team decided to explore whether pre-ART cytokine profiles of those who experience early mortality would differ from those who developed TB-IRIS.

The Study

The study was a secondary analysis of a prospective cohort study conducted in Botswana. Cytokine profiles were measured in all participants after TB treatment initiation but prior to ART initiation. Data gathered included clinical characteristics as well as plasma cytokine, chemokine, and growth factor levels. 

Outcomes were measured up to 6 months after ART initiation and included non-traumatic death as well as a secondary outcome of paradoxical TB-IRIS using a modified clinical case definition of the International Network for Study of HIV-associated IRIS.

The study included 170 patients overall. To be included in the cohort, patients had to be HIV positive ART-naive adults with pre-ART CD4 counts of less than 125 cells/mm³. About two-thirds were men and pregnant women were excluded. Participants had pulmonary TB diagnosed either by smear-microscopy or by the Xpert MTB/RIF test, or they could have had WHO-defined smear-negative pulmonary TB (25%). The median baseline CD4 count was 60 cells/mm³ and a substantial minority had non-TB opportunistic infections (OIs) at baseline.

Participants started standard TB treatment first and then started ART a median of 28 days after TB treatment initiation. 14% started nevirapine-based ART, which in Botswana was almost exclusively reserved for women of reproductive potential during the time of the study. Participants could not have evidence of drug resistance or be taking steroids at the time of study entry. Monthly follow-up was conducted using standardized case definition/case report forms, and any patients who missed a visit were actively traced to their homes. The researchers assessed 29 different biomarkers using Luminex assays.

A total of 120 patients survived after ART initiation without developing TB-IRIS. These individuals served as controls, and their biomarkers and clinical characteristics were compared to those of the 18 patients who experienced early mortality and the 33 to developed paradoxical TB-IRIS (1 of whom died).

Among the 18 participants who died, the median time to death was 49 days. Autopsies were not performed, so it was difficult to definitively say what the cause of death had been, however, these patients had a number of clinical conditions in addition to HIV/TB that the investigators considered likely to have contributed to their deaths, including severe anemia, chronic diarrhea, cryptococcal meningitis, and esophageal candidiasis. There were also concerns about bacteremia and adrenal insufficiency, but the team did not have the diagnostic capacity to investigate in detail.

As noted, there was 1 death among cases of TB-IRIS, in a woman who developed severe dyspnea (shortness of breath) 3 weeks after ART initiation. She was hospitalized and treated with steroids, her dyspnea resolved, and she was discharged after 5 days. Then, 2 weeks later, the patient complained of mouth sores and 2 days after that her family found her dead in her home. The cause of death was unclear, and may not have been due to TB-IRIS.

In an unadjusted analysis of factors associated with each outcome, patients with TB-IRIS were very similar in most respects to control participants who did not develop TB-IRIS and did not die, with the exception of potentially slightly higher baseline body mass index among patients who went on to experience TB-IRIS.

Patients who died were significantly more likely to be women, more likely to start nevirapine-based ART, and had more non-TB OIs. Those who died also had lower baseline CD4 counts (median of 35 cells/mm³ vs 64 cells/mm³ for controls and 61 cells/mm³ for those with TB-IRIS); however, the CD4 ranges overlapped.

Pre-ART cytokine levels were different, however. In general, patients who went on to experience early mortality had higher baseline cytokine values relative to controls.

In a multivariate analysis, after adjusting for baseline CD4 count, female sex, nevirapine use, and the presence of non-TB OIs, high pre-ART levels of the following cytokines were associated with an increased risk of early mortality.

• IL-6; adjusted odds ratio (OR) 3.1;
• IL-10; adjusted OR 3.9;
• MCP-1; adjusted OR 10.9.

In contrast, among patients with TB-IRIS, cytokine levels were low relative to the control patients. In the multivariate analysis (adjusted for baseline body mass index), low levels of GM-CSF, IL-15, IL-12 p70 and p40, IL-6, and IL-17a were each significantly associated with increased risk of TB-IRIS.

Discussion

"Does this is elucidate for us the causal mechanisms of why these patients who started TB treatment and started ART died?" asked Bisson. "It is difficult to say, but it seems relatively clear that these patients died from overwhelming infections, and perhaps they would benefit from more effective antimicrobial therapy."

Another possibility is that patients would have benefited from even earlier ART, which the CAMELIA study suggested would save more lives if it were administered as soon as possible in very advanced HIV/TB patients. Starting ART a median of 28 days after initiation of TB therapy could be too late for some.

As for the TB-IRIS findings, these data are consistent with data from South Africa, showing lower pre-ART cytokine values in patients with TB-IRIS. This suggests that, "Some patients may have an immune defect that's associated with impaired clearance of antigen, that would be manifest as low cytokine values. This may result in a higher antigen load when they start ART they have a higher risk of IRIS," said Bisson.

"The main point here is that advanced HIV/TB is a heterogeneous group, at least according to the tests that we performed prior to ART initiation," Bisson continued. Studies elucidating risk factors for TB-IRIS are trying to identify ways to prevent IRIS, and they are comparing TB-IRIS patients to non-IRIS survivors. "That comes up with risk factors and suggests an intervention such as steroids and NSAIDS, which are tempting to add immunologically. but what if these are then given to all patients including some who are going to go on to die? It's unclear what those effects would [be] on mortality," he concluded.

Reference

S Ravimohan, N Tamuhla, AP Steenhoff, G Bisson, et al. Pre-ART Immunologic Profiles Characterize Risk of Early Mortality and TB-IRIS in HIV/TB Co-infected Adults. 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC 2014). Washington, DC, September 5-9, 2014. Abstract H-1199b.

Source: HIVandHepatitis.com