Antiretroviral therapy (ART) usually wards off HIV-related opportunistic infections (OIs), but a study in the March issue of AIDS reports that almost one third of patients with HIV and certain OIs experienced a flare-up or worsening of their OI within months of starting their first antiretroviral regimen. Paradoxically, these episodes were seen in many of the patients with the best viral load and CD4 cell responses to ART.
Background on IRIS
This pattern of disease after beginning effective ART is called “Immune Reconstitution Inflammatory Syndrome” (IRIS) because it is believed to be the result of the recovering immune system’s belated (and often overly robust) response to an OI.
OIs associated with IRIS may have unusual symptoms and are typically unresponsive to conventional antimicrobial treatment. Often, there is little detectable evidence of the underlying OI surviving in the affected tissues or bodily fluids. Despite this, the inflammatory immune response to the infection can cause serious complications — even death.
There have been many reports of such cases in the medical literature, but estimates on the incidence of IRIS have varied widely. Small and isolated case studies have provided clinicians with little information to help them anticipate which patients might be most likely to develop the syndrome.
A study in Houston
In the present study, the largest of IRIS to date, researchers from the University of Texas and Baylor College in Houston retrospectively investigated the incidence of IRIS among high-risk patients in the Houston area. They also assessed patient’s records for risk factors of developing IRIS, and the long-term outcome of patients with the condition.
The study included HIV-infected patients starting ART who were diagnosed with tuberculosis (TB), M. avium complex (MAC), or C. neoformans between 1997-2000. These conditions are frequently associated with IRIS (other IRIS-associated opportunistic infections were excluded because there was no agreed upon method for case finding).
To be included in the final dataset, patients had to have been prescribed ART, defined as at least three antiretroviral agents, to have a baseline measurement for either CD4 cells or viral load prior to being prescribed ART, and to have at least one follow-up CD4 cell count or viral load after starting ART.
Other data collected included patient demographics, information regarding diagnosis and treatment of the OI, and clinical outcome, including development of IRIS.
To be diagnosed as having IRIS in this study:
- The patient had to be on ART with a rising CD4 cell count and falling viral load
- Prior to starting ART, the patient had to have had a clinical response to treatment of one of the three opportunistic infections listed above.
- Following the initiation of ART, the patient had to have either recurrence of their initial symptoms or new symptoms of an inflammatory process that was not consistent with the usual course of an established infection or a new infection
- All cultures or other lab studies carried out because of the OI ‘flare-up’ had to be negative (in other words, lab studies needed to show that the infection process itself was not spreading or worsening).
- Finally, “the agreement of two investigators was necessary for a diagnosis of IRIS; when there was disagreement or the diagnosis was unclear, then the patient was declared not to have IRIS.”
Results
180 patients included in the final analysis, 86 (47.8%) were infected with M. tuberculosis, 35 (19.4%) with MAC, and 59 (32.8%) with C. neoformans. Patients had quite advanced HIV disease at study entry with median CD4 cell counts (~30) and viral loads ~5.4 log.
IRIS developed during follow-up in 57 of the 180 [31.7%). The absolute number and percentage of patients that developed IRIS while on ART were 26 out of 86 (30.2%) for TB, 11 out of 35 (31.4%) for MAC, and 20 out of 59 (33.9%) for C. neoformans infection. There was no difference in the risk of developing IRIS by OI. The majority of cases of IRIS occurred within the first 60 days of initiating ART.
Differences in patient demographics, such as age, baseline viral load or CD4 cell count, were not associated with the risk of developing IRIS (among these patients who had already contracted an OI). Although men were found to have an increased risk of being diagnosed with IRIS compared with women, this association was not significant when other variables were factored into the analysis.
However, patients who started ART close to the time their OI was first treated were more likely to develop IRIS. The median number of days between beginning OI treatment and ART in patients who developed IRIS was 27 days, while it was 50 days for those who did not develop IRIS (P < 0.001). People who began ART within 30 days of initiating treatment for the opportunistic infection had a relative risk (RR) of 2.01 (95% CI, 1.25–3.22; P 1/4 0.003) for the development of IRIS compared with those who had an interval of longer than 30 days.
The most significant risk factor for developing IRIS was a dramatic drop in viral load. Patients who developed IRIS had much more dramatic reductions (more than 2 logs) in viral load, both initially (within the first 1-90 days) and persistently, than those who did not (P < 0.001). After the first 90 days, patients with IRIS also had significantly greater increases in CD4 cell count. And at 24 months, patients who were still being followed with IRIS were significantly more likely to have a CD4 cell count increase of 100 cells over baseline and viral loads below 400 copies/ml.
However, patients with IRIS had more hospital admissions and were more likely to have invasive medical procedures versus those without IRIS. 39% of patients without IRIS were admitted to the hospital in the first year after starting ART while 81% of patients with IRIS required hospitalization during this same time period (P < 0.001). The percentage of patients who needed an invasive procedure over this 12-month period was 24% for patients without IRIS and 86% for patients with IRIS (P < 0.001). But there was no significant mortality difference between the two groups of patients.
In fact, the authors concluded the survival trend was in favor of the IRIS patients, “which is likely a reflection of the durable viral suppression and immune reconstitution seen in these patients.
Implications
This is one of the first studies of IRIS large enough to draw valid conclusions about its incidence, risk factors, and long-term response to ART. Although the diagnosis of IRIS is subjective, the researchers erred on the side of caution, and if anything, likely underestimated the true incidence of IRIS in such advanced patients.
In the developed world, patients usually start ART with less advanced HIV disease —before developing extensive OIs — and thus would be less likely to develop IRIS. However, this study’s findings may be particularly applicable to resource-limited settings where clinicians need to be alerted to the dangers of IRIS in already ill patients beginning their first antiretroviral regimen.
Shelburne SA et al. Incidence and risk factors for immune reconstitution inflammatory syndrome during highly active antiretroviral therapy. AIDS 19:399–406, 2005.