title: Continued Elevation of Interleukin-18 and Interferon-γ After Initiation of Antiretroviral Therapy and Clinical Failure in a Diverse Multicountry Human Immunodeficiency Virus Cohort.
abstract: Background.We assessed immune activation after antiretroviral therapy (ART) initiation to understand clinical failure in diverse settings.Methods.We performed a case-control study in ACTG Prospective Evaluation of Antiretrovirals in Resource-Limited Settings (PEARLS). Cases were defined as incident World Health Organization Stage 3 or 4 human immunodeficiency virus (HIV) disease or death, analyzed from ART weeks 24 (ART24) to 96. Controls were randomly selected. Interleukin (IL)-6, interferon (IFN)-γ-inducible protein-10, IL-18, tumor necrosis factor-α, IFN-γ, and soluble CD14 (sCD14) were measured pre-ART and at ART24 in plasma. Continued elevation was defined by thresholds set by highest pre-ART quartiles (>Q3). Incident risk ratios (IRRs) for clinical progression were estimated by Poisson regression, adjusting for age, sex, treatment, country, time-updated CD4+T-cell count, HIV ribonucleic acid (RNA), and prevalent tuberculosis.Results.Among 99 cases and 234 controls, median baseline CD4+T-cell count was 181 cells/µL, and HIV RNA was 5.05 log10cp/mL. Clinical failure was independently associated with continued elevations of IL-18 (IRR, 3.03; 95% confidence interval [CI], 1.27-7.20), sCD14 (IRR, 2.17; 95% CI, 1.02-4.62), and IFN-γ (IRR, 0.08; 95% CI, 0.01-0.61). Among 276 of 333 (83%) who were virologically suppressed at ART24, IFN-γ was associated with protection from failure, but the association with sCD14 was attenuated.Conclusions.Continued IL-18 and sCD14 elevations were associated with clinical ART failure. Interferon-γ levels may reflect preserved immune function.
authors: Johns Hopkins University School of Medicine , Baltimore, Maryland.
authors: Ashwin
authors: A
authors: Balagopal
authors: Johns Hopkins University School of Medicine , Baltimore, Maryland.
authors: Nikhil
authors: N
authors: Gupte
authors: Johns Hopkins University School of Medicine , Baltimore, Maryland.
authors: Rupak
authors: R
authors: Shivakoti
authors: Johns Hopkins University School of Medicine , Baltimore, Maryland.
authors: Andrea L
authors: AL
authors: Cox
authors: Johns Hopkins University School of Medicine , Baltimore, Maryland.
authors: Wei-Teng
authors: WT
authors: Yang
authors: Malawi College of Medicine-Johns Hopkins University Research Project , Blantyre , Malawi.
authors: Sima
authors: S
authors: Berendes
authors: University of Witwatersrand , Johannesburg , South Africa.
authors: Noluthando
authors: N
authors: Mwelase
authors: University of North Carolina Project, Kamuzu Central Hospital , Lilongwe , Malawi.
authors: Cecilia
authors: C
authors: Kanyama
authors: Nelson Mandela School of Medicine , University of KwaZulu-Natal , Durban , South Africa.
authors: Sandy
authors: S
authors: Pillay
authors: University of Zimbabwe, College of Health Sciences , Harare.
authors: Wadzanai
authors: W
authors: Samaneka
authors: Hospital Nossa Senhora de Conceição , Porto Alegre , Brazil.
authors: Breno
authors: B
authors: Santos
authors: Y.R.G.Care , Chennai , India.
authors: Selvamuthu
authors: S
authors: Poongulali
authors: National AIDS Research Institute , Pune , India.
authors: Srikanth
authors: S
authors: Tripathy
authors: Les Centres GHESKIO , Port-Au-Prince , Haiti.
authors: Cynthia
authors: C
authors: Riviere
authors: Asociación Civil Impacta Salud y Educación (IMPACTA) Peru Clinical Trials Unit , Lima.
authors: Javier R
authors: JR
authors: Lama
authors: Instituto de Pesquisa Clínica Evandro Chagas, Fundação Oswaldo Cruz , Rio de Janeiro , Brazil.
authors: Sandra W
authors: SW
authors: Cardoso
authors: Research Institute for Health Sciences, Chinag Mai University, Thailand.
authors: Patcharaphan
authors: P
authors: Sugandhavesa
authors: Johns Hopkins University School of Medicine , Baltimore, Maryland.
authors: Richard D
authors: RD
authors: Semba
authors: University of Zimbabwe, College of Health Sciences , Harare.
authors: James
authors: J
authors: Hakim
authors: University of North Carolina Project, Kamuzu Central Hospital, Lilongwe, Malawi; University of North Carolina, Chapel Hill.
authors: Mina C
authors: MC
authors: Hosseinipour
authors: Y.R.G.Care , Chennai , India.
authors: Nagalingeswaran
authors: N
authors: Kumarasamy
authors: University of Witwatersrand , Johannesburg , South Africa.
authors: Ian
authors: I
authors: Sanne
authors: University of California Davis, Sacramento.
authors: David
authors: D
authors: Asmuth
authors: University of Colorado School of Medicine, Colorado.
authors: Thomas
authors: T
authors: Campbell
authors: Johns Hopkins University School of Medicine , Baltimore, Maryland.
authors: Robert C
authors: RC
authors: Bollinger
authors: Johns Hopkins University School of Medicine , Baltimore, Maryland.
authors: Amita
authors: A
authors: Gupta
keywords: HIV; IFN-γ; IL-18; antiretroviral therapy; immune activation; inflammasome