Markers of immune activation and viral load in HIV-associated sensory neuropathy. Neurology

Department of Neurology, University of Rochester, 601 Elmwood Ave., Box 673, Rochester, NY 14642, USA.
Neurology (Impact Factor: 8.29). 04/2005; 64(5):842-8. DOI: 10.1212/01.WNL.0000152981.32057.BB
Source: PubMed


HIV infection is associated with a painful distal sensory polyneuropathy (DSP) that can severely limit the quality of life of affected subjects. The pathogenesis of DSP is unknown, although both HIV proteins and products of immune activation triggered by HIV infection have been implicated.
To assess the association between baseline markers of immune activation and HIV RNA levels (viral load) and time to symptomatic DSP (SDSP).
A cohort of 376 subjects, most receiving highly active antiretroviral therapy (HAART), were followed semiannually for up to 48 months. Blood and CSF levels of HIV viral load, monocyte chemotactic protein-1, macrophage colony-stimulating factor (M-CSF), matrix metalloproteinase-2, and tumor necrosis factor-alpha were measured in addition to CD4 lymphocyte cell count.
In subjects without SDSP at baseline (62.5% of the cohort), among the virologic and immunologic markers, only baseline CSF M-CSF levels were associated with time to SDSP (hazard ratio = 2.97, p = 0.05). The Kaplan-Meier estimate of the 1-year incidence of SDSP was 21%, a 15% decrease from that observed in the Dana cohort, a pre-HAART cohort enrolled with the same inclusion/exclusion criteria.
Highly active retroviral therapy (HAART) has changed the natural history of HIV-associated symptomatic distal sensory polyneuropathy (SDSP), which may explain, in contrast with studies from the pre-HAART era, the lack of association between SDSP and baseline HIV viral load and CD4 cell count.

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    • "Few studies have assessed the role of cytokines in HIV-1-associated DSP. In a cross-sectional cohort, largely on cART, several markers of immune activation in the plasma and cerebrospinal fluid (CSF) were studied; only CSF macrophage colony-stimulating factor levels predicted time to developing symptomatic DSP [18]. A study of cytokine gene polymorphisms in individuals with DSP after cART initiation, with or without symptoms, showed an association with the TNFA-locus [19]. "
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    ABSTRACT: 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. 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. 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). The initiation of cART in previously treatment naive 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.
    Full-text · Article · Feb 2014 · BMC Infectious Diseases
    • "The most common symptom of the HIV-associated PNs is numbness and the most disabling aspect is neuropathic pain. Up to one third of subjects with PN signs suffer from pain (Schifitto et al. 2005; Tagliati et al. 1999). Examination reveals stocking-pattern impairments of pain, temperature, and vibratory sensation, with decreased or absent ankle jerks (Cornblath and McArthur 1988). "
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    ABSTRACT: For any practitioner treating patients with human immunodeficiency virus (HIV), this chapter provides a framework for considering the varied array of neurological complications. HIV can affect both central and peripheral nervous systems. Some of these complications, such as HIV-associated neurocognitive dysfunction, are the direct result of HIV itself. Other complications are due to opportunistic infections or are adverse effects of the treatments that are used against HIV. The clinical manifestations of these complications are reviewed, with emphasis on the key features useful for making proper and timely diagnoses. Up-to-date treatment recommendations, based on the most recent research and expert opinion, are included.
    No preview · Chapter · Jan 2013
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    • "This is consistent with existing evidence (Lichtenstein et al. 2005; Schifitto et al. 2005). Even though some antiretroviral drugs can cause new or worsen pre-existing peripheral neuropathy, overall, ART has been shown to reduce the likelihood and severity of neuropathy in HIV-positive patients (Lichtenstein et al. 2005; Schifitto et al. 2005). In the developed world, several studies show that initiation of ART is associated with improvement in cognitive and peripheral nervous system function (Robertson et al. 2011). "
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    ABSTRACT: Peripheral neuropathy (PN) is associated with advanced HIV disease and may be a complication of antiretroviral therapy (ART) or anti-tuberculosis (TB) drugs, specifically isoniazid (INH). The effect of non-ART-drug-related PN on treatment outcomes is yet to be determined. We analysed prospectively collected cohort data for HIV-infected ART-naive adults initiating ART at the Themba Lethu Clinic, Johannesburg, South Africa from June 2004 to June 2009. Patients who presented with signs and symptoms of numbness or dysesthesia prior to initiation of ART were defined as having PN. Cox proportional hazard models were used to estimate the effect of PN alone (HIV-related PN) or PN with a history of INH use (TB-related PN) on mortality, lost to follow-up (LTFU), persistent and recurrent PN by 12 months of follow-up. Of the 9,399 patients initiating ART, 3.9 % had HIV-related PN while a further 1.8 % had TB-related PN. Patients with PN did not have a significantly higher risk of mortality compared to those without PN (hazard ratio (HR) 1.17 95 % CI 0.92-1.49). Patients with TB-related PN were less likely to be LTFU by 12 months (HR 0.65 95 % CI 0.44-0.97) compared to those without PN. Patients with HIV-related PN were at increased risk of persistent PN at 3 months post-ART initiation. Patients with HIV-related PN had a similar risk of recurrent PN compared to those with TB-related PN (HR 1.28 95 % CI 0.72-2.27). We demonstrate that patients with PN at initiation of ART present with advanced HIV disease. Completion of TB treatment may reduce the risk of persistent PN in patients with TB-related PN. Use of HIV drugs, even neurotoxic ones, may overall limit neuropathy.
    Full-text · Article · Apr 2012 · Journal of NeuroVirology
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