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Open Access Research article

Plasma cytokine profiles in HIV-1 infected patients developing neuropathic symptoms shortly after commencing antiretroviral therapy: a case-control study

Johan J Van der Watt1*, Katalin A Wilkinson234, Robert J Wilkinson2345 and Jeannine M Heckmann1

Author Affiliations

1 Division of Neurology, Department of Medicine, University of Cape Town, Observatory, Cape Town 7925, South Africa

2 Department of Medicine, University of Cape Town, Observatory, Cape Town 7925, South Africa

3 Clinical Infectious Diseases Research Initiative, Institute of Infectious Diseases and Molecular Medicine, University of Cape Town, Observatory, Cape Town 7925, South Africa

4 Division of Mycobacterial Research, MRC National Institute for Medical Research, London NW7 1AA, UK

5 Division of Medicine, Imperial College London, London W2 1PG, UK

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BMC Infectious Diseases 2014, 14:71  doi:10.1186/1471-2334-14-71

Published: 10 February 2014

Abstract

Background

In patients infected with human immunodeficiency virus 1 (HIV-1) neuropathic symptoms may develop within weeks of starting combination antiretroviral therapy (cART). This timing coincides with the occurrence of immune reconstitution inflammatory syndrome. Our objective was to investigate the longitudinal association of plasma cytokine and soluble receptor concentrations with incident neuropathic symptoms within 12 weeks of starting programme-based cART in a nested case-control study.

Methods

One hundred and twenty adults without neuropathic symptoms and about to initiate cART were followed longitudinally for 24 weeks after cART initiation. Subjects were examined for peripheral neuropathy at baseline (pre-cART) and 2-, 4-, 12- and 24 weeks thereafter. Individuals developing neuropathic symptoms within 12 weeks of starting cART were matched in a nested case-control design with those remaining symptom-free for at least 24 weeks. Plasma was collected at each visit. Cytokines and soluble receptors were quantified using multiplex immunometric assays.

Results

Incident neuropathic symptoms occurred in 32 (27%) individuals within 12 weeks of starting cART for the first time. Cytokine concentrations increased at 2 weeks, irrespective of symptom-status, returning to baseline concentrations at 12 weeks. Compared to the control group, the symptomatic group had higher baseline levels of interleukin-1 receptor (IL-1R)-antagonist. The symptomatic group also showed greater increases in soluble interleukin-2 receptor-alpha and tumour necrosis factor (TNF) receptor-II levels at week 2 and soluble interleukin-6 receptor levels at week 12. Ratios of pro-inflammatory- vs anti-inflammatory cytokines were higher for TNF-alpha/IL-4 (p = 0.022) and interferon-gamma/IL-10 (p = 0.044) in those developing symptoms. After 24 weeks of cART, the symptomatic group showed higher CD4+ counts (p = 0.002).

Conclusions

The initiation of cART in previously treatment naïve individuals was associated with a cytokine 'burst’ between 2- and 4 weeks compared with pre-cART levels. Individuals developing neuropathic symptoms within 12 weeks of starting cART showed evidence of altered cytokine concentrations even prior to initiating cART, most notably higher circulating IL-1R-antagonist levels, and altered ratios of “pain-associated” cytokine and soluble receptors shortly after cART initiation.

Keywords:
HIV neuropathy; Sensory neuropathy; Neuropathic symptoms; Antiretroviral toxicity; Cytokines; Immune reconstitution; Interleukin-1 receptor antagonist