Early immunologic failure is associated with early mortality among advanced HIV-infected adults initiating antiretroviral therapy with active tuberculosis

Abstract

Background: The relationship between antiretroviral therapy (ART) response and early mortality after ART initiation is unknown. We hypothesized that early mortality is associated with decreased early immunologic response to ART.

Methods: We prospectively determined the association between changes in plasma human immunodeficiency virus type 1 (HIV-1) RNA and CD4(+) T-cell counts (CD4 count) after 4 weeks of ART and early mortality in adults with pulmonary tuberculosis and pre-ART CD4 counts ≤ 125 cells/µL. Purified protein derivative (PPD)-specific immune recovery was determined by interferon-γ enzyme-linked immunosorbent spot assays. Levels of interleukin 6, C-reactive protein, and soluble CD14 were assessed. Patients with CD4 count and viral load values at baseline and week 4 were analyzed using multiple logistic regression.

Results: Early immunologic response, but not pre-ART CD4 counts or virologic response, was related to early mortality (8 [interquartile range {IQR}, -18 to 43] vs 68 [IQR, 24-131] cells/µL, P = .002). In a logistic regression model, every 20 cells/µL increase in the CD4 count from baseline to week 4 was independently associated with a 40% reduction in the odds of death (odds ratio, 0.59 [95% confidence interval, .41-.87]). PPD-specific immune recovery was lower, whereas levels of immune activation were higher, among deaths.

Conclusions: Early immunologic failure despite virologic suppression is associated with early mortality after ART initiation in advanced HIV/tuberculosis.

Keywords: CD4 counts; HIV/AIDS; antiretroviral therapy; early mortality; immune activation; immune recovery; pathogen-specific immune recovery; sub-Saharan Africa; tuberculosis.

Figure 1.

Virologic and immunologic response. Baseline CD4 counts and virologic suppression did not differ between those who died and those who survived. Change in HIV plasma viral load (VL) from baseline was not significantly different comparing patients who died (n = 9) to those who survived (n = 87; P = .58) (A). No marked differences in absolute VL at baseline (P = .50) and week 4 after antiretroviral therapy initiation (P = .89) were observed comparing those who died (B) to those who survived (C). Change in CD4 counts from baseline was significantly lower in patients who died (n = 9) vs survived (n = 87; P = .002) (D). No significant differences in CD4 count were observed at baseline (P = .88), whereas absolute week 4 CD4 counts were lower among those who died (E) vs survivors (F; P = .004). Abbreviations: HIV, human immunodeficiency virus; VL, viral load.

Figure 2.

Pathogen-specific immune response. Change in purified protein derivative (PPD) from baseline in those who died (n = 5) was lower compared to those who survived (n = 51; P = .10) (A). PPD-specific response at baseline trended to be lower, but not statistically significant, among those who died (B) compared to those who survived (C; P = .70), whereas absolute week 4 PPD-specific responses were significantly lower among those who died vs survivors (P = .039). Change in HIV Gag–specific response from baseline (D; P = .90) as well as absolute baseline (P = .37) and week 4 after antiretroviral therapy initiation (P = .34) values trended to be lower among those who died (E) compared to survivors (F), but were not statistically significant. *Difference in y-axis scale to increase resolution. Abbreviations: HIV, human immunodeficiency virus; PBMC, peripheral blood mononuclear cell; PPD, purified protein derivative; SFU, spot-forming units.