Recovery of polyfunctional TB-specific CD4 cells boosted chances of tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) after antiretroviral therapy (ART) began in a case-control study of 143 people with active TB . The finding adds to the understanding of this dangerous syndrome in people starting ART with active TB.
Several studies show that ART started soon after anti-TB therapy begins promotes survival in people with advanced TB and HIV. But early ART in such patients boosts the risk of paradoxical TB-IRIS, which can require hospital admission, invasive procedures, and corticosteroid therapy. Previous research yielded conflicting results on whether cell-mediated immune responses play a part in the pathogenesis of TB-IRIS. Researchers from the University of Pennsylvania conducted this study to test the hypothesis that "rapid reconstitution of TB-specific polyfunctional CD4 T-cell response on ART is associated with TB-IRIS."
The study involved HIV/TB-coinfected people enrolled in a prospective cohort study in Botswana. All participants had a CD4 count below 125, and none had taken antiretroviral therapy. All were scheduled to start ART within 2 months of starting anti-TB therapy. No one had evidence of drug-resistant TB, and no one was pregnant or taking steroids.
The primary outcome was TB-IRIS within 6 months of starting ART, and the main exposure variable was change in polyfunctional (IFN-gamma+, TNF-alpha+, IL-2+) CD4-cell response from baseline to 4 weeks after starting ART. Cases were patients who had TB-IRIS within 6 months of starting ART, and controls were survivors without TB-IRIS.
The 31 cases and 112 controls did not differ in proportion of women (45% and 41%), average age (37 and 36), median time to starting ART (30 and 27 days), or baseline CD4 count (62 and 66) or viral load (5.4 and 5.5 log copies). A higher proportion of cases than controls started a nevirapine-based regimen (23% versus 9%, P = 0.04), and a lower proportion of cases had a body mass index below 19 kg/m(2) (32% versus 51%, P = 0.06). Only 1 of 31 people with TB-IRIS died, and no one received corticosteroids. At baseline cases had a higher frequency of effector memory CD8 cells than controls (P = 0.04), but otherwise cases and controls did not differ in baseline or week 4 memory CD4 or CD8 cells or immune activation of CD4 or CD8 cells.
The researchers could measure change from baseline in levels of polyfunctional CD4-cell responses in 8 cases and 37 controls. In those patients the frequency of TB-specific polyfunctional CD4-cell responses increased significantly more in cases than controls (median 0.38% versus 0.03%, P = 0.02). Logistic regression analysis indicated that every quartile increase in TB-specific polyfunctional responses meant a 2.8-fold increase in odds of TB-IRIS (95% confidence interval [CI] 1.1 to 7.5). Polyfunctional response level 4 weeks after ART began was associated with 3.5 times higher odds of TB-IRIS (adjusted odds ratio 3.5, 95% CI 1.4 to 8.8).
The University of Pennsylvania team concluded that "robust recovery of polyfunctional TB-specific CD4 T cells is independently associated with paradoxical TB-IRIS." They cautioned that broadly suppressive therapies to prevent TB-IRIS in HIV/TB patients "may impede recovery of host protective T-cell responses known to combat TB." But they suggested a "potential role" for anti-TNF-alpha immunotherapy to treat severe TB-IRIS.
1. Ravimohan S, Tamuhla N, Nfanyana K, et al. Reconstitution of polyfunctional TB-specific CD4+ T-cells in TB-IRIS. ICAAC 2015, September 17-21, 2015, San Diego.