Restored TB-specific CD4 response linked to TB-IRIS soon after ART starts
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 [1].
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.
Reference
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.
Source:
NATAP
