Continued elevation of interleukin-18 and interferon-γ after initiation of antiretroviral therapy and clinical failure in a diverse multicountry human immunodeficiency virus cohort

Post Date: 
2016-07-27
Publication: 
Open Forum Infectious Diseases
Summary: 

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 log10 cp/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.

Citation: 
Balagopal A, Gupte N, Shivakoti R, Cox AL, Yang W, Berendes S, Mwelase N, Kanyama C, Pillay, Samaneka W, Santos B, Poongulali S,Tripathy S, Riviere C, Lama JR, Cardoso SW, Sugandhavesa P, Semba RD, Hakim J, Hosseinipour M, Kumarasamy N, Sanne I, Asmuth D, Campbel T, Bollinger RC, Gupta A. Continued elevation of interleukin-18 and interferon-γ after initiation of antiretroviral therapy and clinical failure in a diverse multicountry human immunodeficiency virus cohort. Open Forum Infect Dis. 2016 Jul 27;3(3):ofw118. eCollection 2016 Sep. PMID: 27800521; PMCID: PMC5084713.
Collaborators: 
  • Malawi College of Medicine-Johns Hopkins University Research Project, Blantyre, Malawi
  • University of Witwatersrand, Johannesburg, South Africa
  • University of North Carolina Project, Kamuzu Central Hospital, Lilongwe, Malawi
  • Nelson Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
  • University of Zimbabwe, College of Health Sciences, Harare
  • Hospital Nossa Senhora de Conceição, Porto Alegre, Brazil
  • Y.R.G. Care, Chennai, India
  • National AIDS Research Institute, Pune, India
  • Les Centres GHESKIO, Port-Au-Prince, Haiti
  • Asociación Civil Impacta Salud y Educación (IMPACTA) Peru Clinical Trials Unit, Lima
  • Instituto de Pesquisa Clínica Evandro Chagas, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil
  • Research Institute for Health Sciences, Chinag Mai University, Thailand
  • University of North Carolina Project, Kamuzu Central Hospital, Lilongwe, Malawi; University of North Carolina, Chapel Hill
  • University of California Davis, Sacramento
  • University of Colorado School of Medicine, Colorado