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Painful HIV-associated sensory neuropathy
Practice Points
Catherine Louise Cherry*1,2, Antonia L Wadley2 & Peter R Kamerman2 Sensory neuropathy is a frequent complication of HIV and many affected patients suffer from
neuropathic pain. HIV-associated sensory neuropathy (HIV-SN) risk factors include advanced HIV disease, exposure to
neurotoxic antiretroviral drugs, factors associated with neuropathy risk in any setting (age, height, diabetes and so on) and genetic factors (including genes associated with inflammation). Neuropathic pain is the major driver of morbidity in HIV-SN. The determinants of HIV-SN pain are not well described and evidence-based analgesic options are lacking. Animal models support a role for inflammation in the pain of HIV-SN, whether triggered by viruses,
neurotoxic medication or a combination of both. The available data suggest that painful HIV-SN will remain common, even in cohorts never exposed to
neurotoxic antiretroviral medications. Future research needs to include epidemiologic work and genetic studies (to understand the size of the
problem and associations with HIV-SN pain in the context of modern HIV management), development of optimized laboratory models incorporating active viral replication and currently recommended antiretroviral agents, and clinical trials of both prevention and management strategies for HIV-SN.
SUMMARY Painful HIV-associated sensory neuropathy (HIV-SN) is an early recognized neurological complication of HIV. The introduction of effective HIV treatments saw increased rates of HIV-SN, with some antiretrovirals (notably stavudine) being neurotoxic. Although neurotoxic antiretrovirals are being phased out, the available data suggest that incident HIV-SN will remain common, impairing quality of life, mobility and ability to work. Despite its major clinical importance, the pathogenesis and determinants of pain in HIV-SN are poorly understood, and effective prevention and analgesic strategies are lacking. Here, we review what is known about the rates and risk factors for painful HIV-SN, the laboratory models informing our understanding of neuropathic pain in HIV, and the future clinical and laboratory work needed to fully understand this debilitating condition and provide effective management strategies for those affected. Infectious Diseases Unit, The Alfred Hospital, Centre for Virology, Burnet Institute; and Faculty of Medicine, Nursing & Health Sciences, Monash University, Commercial Road, Melbourne, Victoria 3004, Australia 2 Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of Witwatersrand, South Africa *Author for correspondence: Tel.: +61 3 9076 2000; Fax: +61 3 9076 2431; [email protected] 1
10.2217/PMT.12.67 © 2012 Future Medicine Ltd
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SPECIAL REPORT Cherry, Wadley & Kamerman Sensory neuropathy (SN) is a common complication of HIV and some HIV treatments [1–4]. Most patients with symptomatic HIV-associated SN (HIV-SN) experience neuropathic pain [1–3,5] with consequent impairment of mood, physical function, quality of life and ability to work [1,6–8]. The morbidity associated with HIV-SN is further magnified by the lack of evidence-based analgesic options for affected patients [9]. The high disease burden and lack of effective treatments makes HIV-SN painful. This is a problem that warrants urgent attention; a better understanding of the pathogenesis of HIV-SN and the painful symptoms of the neuropathy will be critical in designing effective prevention and management strategies. Epidemiology of HIV-SN It is not fully understood why some individuals with HIV develop SN and others with similar exposures do not. However, some epidemiologic factors have been described (reviewed recently in [10], including discussion of the lack of a ‘gold standard’ method for diagnosing HIV-SN that complicates understanding of this topic). In the era before combination antiretroviral therapy (cART) was available, HIV-SN was primarily a complication of advanced HIV. Prevalence rates were low (1.5%) in air force recruits identified to be HIV infected [11]. They rose to around 13% in ambulatory HIV-care clinic populations [12,13] and were highest (35%) among hospitalized patients with AIDS [14]. The association between HIV-SN risk and advanced HIV was prominent, despite some differences in how HIV-SN was defined by various authors. Following the introduction of effective HIV treatments, rates of HIV-SN increased, at least in part, because of the neurotoxicity of some antiretroviral medications (notably the neurotoxic nucleoside analog reverse transcriptase inhibitors [NRTIs] stavudine, didanosine and zalcitabine) [3]. Very high rates of symptomatic HIV-SN (up to 57% [2]) have been described in diverse cohorts since the introduction of cART, with exposure to stavudine – the most widely used of the neurotoxic NRTIs – typically found to be a significant risk factor [2,3,15–21]. It has been widely hypothesized that NRTI side effects, including neuropathy, are attri butable to the mitochondrial toxicity of these drugs [22–26]. Polymorphisms in mitochondrial DNA have been independently associated with
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HIV-SN among patients of European [27,28] and African–American [29] descent. The possible contribution to HIV-SN risk of nuclear DNA polymorphisms that affect mitochondrial function has also been considered. For example, genes involved in iron transport (essential to healthy mitochondrial function) have been associated with increased SN risk in patients exposed to neurotoxic NRTIs [30]. Initial explor ation of polymorphisms in the gene encoding mitochondrial polymerase g found no association between HIV-SN and the number of CAG repeats in one small study [31]. Other polymorphisms in this gene, including some that have been linked to other neurological diseases, have not yet been examined for any association with HIV-SN risk and warrant investigation [32]. In addition, hypothesis-free genome-wide studies (rather than only hypothesis-driven candidate gene studies) would inform our understanding of both the mechanisms and risk factors for HIV-SN. Factors that increase risk of peripheral neuro pathy in other settings have generally also been associated with HIV-SN risk, independent of whether or not the patient has been exposed to neurotoxic NRTIs. For example, increasing age is one of the most consistently observed risk factors for SN among people living with HIV [2,3,18,33,34]. Similarly, increasing height [2,18], the presence of diabetes mellitus [34,35] and exposure to isoniazid [5,17,20] have all been found to associate with HIV-SN. A range of other associations with HIV-SN risk are also described. Consistent with HIV-SN rates increasing with disease progression among those with untreated HIV, a lower nadir CD4 count has been described as a risk factor for HIV-SN in some cART-treated cohorts [33]. Ethnicity may be important, with studies undertaken in Africa typically finding higher HIV-SN prevalence rates than those performed elsewhere [10]. We find, using identical methods at sites in five countries, that symptomatic HIV-SN prevalence is increased among black people (data currently published in abstract form) [36]. However, when SN has been defined on the basis of neuropathic signs alone, increased risk has not been consistently associated with a particular ethnic group [15,34,37]. It is possible that antiretroviral medications (other than the neurotoxic NRTIs) may increase HIV-SN risk, notably protease inhibitors [3,38,39], although this also remains controversial [15,40].
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Painful HIV-associated sensory neuropathy Several pieces of evidence point to a likely role for the host inflammatory response in HIV-SN risk, whether triggered by HIV itself, HIV treatments or a combination of both. Firstly, accumulation of activated macrophages in the nervous system has been documented in all neurological diseases associated with untreated HIV and can occur despite advanced immune suppression [41,42]. Increased levels of TNF-a and reduced levels of IL-4 were also documented in peripheral nerves from six patients with HIV-SN, but not neuropathy-free individuals with HIV [43]. HIV-SN occurring in the context of antiretroviral therapy is clinically similar to that seen in untreated HIV, suggesting possible shared mechanisms. Consistent with this, cytokine genot ype (notably alleles of TNFA), has been associated with HIV-SN in stavudine-treated patients and changes in chemokine levels with cART initiation may be predictive of HIV-SN [44–46]. Epidemiology of painful HIV-SN The majority of patients with symptomatic HIV-SN experience pain [1–3,5]. Despite this, there has been relatively little work done to understand the epidemiology of painful HIV-SN; a particularly surprising evidence gap considering the central importance of neuropathic pain to the burden of disease [47]. The negative impact of HIV-SN pain on the lives of patients was highlighted in a 2010 publication from the US-based CHARTER study. The authors presented HIV-SN prevalence data from a cohort of 1539 adults with HIV attending six hospital-based HIV care clinics [1]. Of 536 patients found to have symptomatic SN, 335 (62.5%) had neuropathic pain. In this cohort, neuropathic pain was independently associated with unemployment (odds ratio: 1.58, 95% CI: 1.18–2.11), dependence in activities of daily living (odds ratio: 2.29, 95% CI: 1.72–3.04), reduced quality of life and current evidence of a major depressive disorder (odds ratio: 1.95, 95% CI: 1.45–2.6). More severe pain was associated with a greater likelihood of being unemployed, more frequent dependence and poorer quality of life [1]. Another recent US-based study has confirmed that the severity of neuropathic pain in HIV-SN correlates independently with each of pain-related disability, depressive symptoms and catastrophizing (a negative emotional and cognitive response to pain characterized by magnification [belief that things are worse than they are], rumination and helplessness) [48].
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Maladaptive cognitive processes, including negative self-statements and negative social cognitions, associate with increased pain intensity in HIV-SN, as is true in other painful conditions [49]. Pain is clearly central to the clinical impact of HIV-SN. Several pieces of data suggest that pain in HIV-SN may be a function of the severity of nerve dysfunction and damage. For example, psychophysical testing has demonstrated greater hypoesthesia to non-noxious warm stimuli in patients with painful HIV-SN compared with patients with nonpainful HIV-SN. Only patients with pain were hypersensitive to noxious cold (reduced pain threshold) and noxious static mechanical stimuli (reduced pain threshold and increased pain response to suprathreshold stimuli) [50,51]. Indeed, the degree of pain hypersensitivity to static mechanical stimuli correlated with the intensity of patients’ spontaneous pain [50]. At least three studies have demonstrated an inverse relationship between intraepidermal nerve fiber density at the distal leg (a reliable measure of small diameter nerve die-back [52,53]) and severity of pain in patients with HIV-SN [54–56]. In the CHARTER cohort, increasingly severe neuropathic pain was also associated with increased numbers of abnormal neurological signs [1]. Among the subset of patients with detectable viremia at baseline in the AIDS Clinical Trials Group protocol 291, more severe pain and abnormal sensory testing thresholds both associated with higher plasma HIV viral loads – again, supporting an association between pain and the degree of nerve damage [54]. Although the above evidence points to the severity of nerve injury and dysfunction as a major predictor of pain in HIV-SN, the exact nature of the algogenic processes involved has not been fully resolved. Our own recent work examining a possible role for polymorphisms in the CGH1 gene in HIV-SN pain was negative [57]. Previous genetic studies, while providing indirect evidence of possible pathogenic processes involved in HIV-SN, have not generally reported whether or not the candidate genes considered were associated with pain [27–30,44,58]. Post-mortem studies of neural tissues did not attempt to correlate observed pathologies with the presence and severity of pain during life [41,42,59–61]. Similarly, few epidemiologic studies have addressed the question of whether risk factors for painful HIV-SN are the same as those associated with symptomatic HIV-SN
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SPECIAL REPORT Cherry, Wadley & Kamerman in general. Indeed, the CHARTER study suggests the possibility of epidemiologic associations peculiar to painful HIV-SN, with a higher nadir CD4 T-cell count independently associated with pain among patients with neuropathic signs [1]. Therefore, we must currently look to laboratory models for evidence supporting proposed pathogenic mechanisms for pain in HIV-SN. Mechanisms of pain in HIV-SN The establishment of chronic neuropathic pain involves maladaptive changes in the peripheral and the CNS that produce and maintain a hypersensitive pain state [62]. Laboratory models of HIV-SN demonstrate that both viral particles (including viral coat glycoprotein gp120 and viral accessory protein Vpr) and neurotoxic NRTIs (especially zalcitabine) are able to induce thermal and/or mechanical hypersensitivity, including some of the maladaptive changes demonstrated in other models of neuropathic pain [63]. These in vivo and in vitro data are summarized in Table 1 and described in more detail below. HIV-induced hypernociception
Gp120 and Vpr induced hyperexcitability characterized by increased intracellular calcium and changes in membrane potential in cultured dorsal root ganglion (DRG) cells [64,65]. In the case of gp120, these changes involved activation of CXCR4/CCR5 chemokine receptors on cells, and the majority of responsive cells were capsaicin sensitive. It has been hypothesized that this neuronal hyperexcitability may contribute to development of chronic pain through activitydependent sensitization of nociceptive pathways and/or neuronal loss. In animal models, gp120 and Vpr have been shown to induce sustained algogenic changes in the peripheral nerve trunk, DRG and spinal cord dorsal horn [64–70]. For example, exposure of a segment of the rat sciatic nerve to gp120 was associated with acute macrophage infiltration and inflammatory cytokine secretion at the site of exposure [69,70]. This localized inflammation correlated with secondary die-back of intraepidermal nerve fibers [68] (a clinical feature correlated with pain intensity in HIV-SN [54–56]) and inflammatory changes in the DRG (increased TNF-a and CCL2 secretion, and CCR2 expression on sensory neurons) and dorsal horn of the spinal cord (gliosis and increased TNF-a secretion). These inflammatory changes are characteristic of changes observed in other
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models of neuropathic pain [62], and their importance in the pathogenesis of gp120-induced hypernociception is supported by the ability to reverse tactile nociception with administration of a CCR2 receptor antagonist [67] and reduce it by central blockade of TNF-a [66]. Similar to the changes observed in gp120 models, immunodeficient mice expressing the Vpr transgene (vpr/R AG1(-/-) mice) developed mechanical hypersensitivity, which was associated with increased IFN-a expression in the dorsal horn and nerve trunk, and death of DRG neurons [65]. Thus, viral-mediated inflammatory reactions in peripheral nerves and their sequelae in the DRG and spinal cord are sufficient to drive the development of hypernociception in animal models of painful HIV-SN. Hypernociception induced by
antiretroviral drugs
The algogenic mechanisms of treatment-related hypernociception have mainly been studied in animals administered the highly neurotoxic NRTI zalcitabine, which is no longer used therapeutically [69,71]. Consistent with the known ability of NRTIs to inhibit mitochondrial function, the hypernociception following a single intravenous injection of zalcitabine in rats was associated with mitochondrial-dependent activation of proapoptotic caspase pathways [71,72]. In addition, like the algogenic processes induced by viral particles, zalcitabine administration induced inflammatory changes in the DRG and spinal cord dorsal horn. Zalcitabine administration resulted in Schwanncell activation and macrophage infiltration of the DRG, which was associated either with secretion of pronociceptive chemokines, CCL2 (repeated dosing schedule) [69] or CXCL12 (single administration) [73]. With CXCL12 expression, there was also an increase in expression of its receptor, CXCR4, on DRG neurons. Thus, blocking the receptor suppressed zalcitabine-induced hypernociceptive behavior [73]. The dosing schedule of NRTI to animals (repeated vs single administration) may be critical to their effect on algogenic spinal dorsal horn changes. Thrice-weekly zalcitabine dosing for 3 weeks induced hypernociception in rats that was not associated with significant dorsal horn gliosis and was not prevented by inhibitors of glial activation [69]. Conversely, a single administration of high-dose zalcitabine to rats induced significant astrocytosis and TNF-a expression in the dorsal horn, and hypernociception that
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Painful HIV-associated sensory neuropathy
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Table 1. Algogenic processes in animal models of HIV-associated sensory neuropathy. Sensory Peripheral nerve fiber axon neuropathy type Virus-related
Drug-related
Dorsal root ganglion
Dorsal horn of the spinal cord
Macrophage infiltration Secretion of inflammatory cytokines (TNF-a and IFN-a) Increased membrane excitability
Schwann-cell activation and macrophage infiltration Secretion of inflammatory cytokines (TNF-a and IFN-a) and chemokines (CCL2) Increased membrane excitability Neuronal loss Activation of caspase-dependent Schwann-cell activation and macrophage infiltration nociceptive pathways secondary Secretion of proinflammatory chemokines (CCL2 and to mitochondrial dysfunction CXCL12) Expression of CCR2 and CXCR4 receptors on dorsal root ganglion neurons Secretion of TNF-a by dorsal root ganglion neurons
Microgliosis and astrocytosis Secretion of TNF-a
Astrocytosis Secretion of TNF-a Secretion of BDNF
Adapted from [63].
could be reversed by blocking TNF-a [74]. Oneoff administration of stavudine to mice induced mechanical hypersensitivity that correlated with expression of BDNF in the dorsal horn [75]. These data show that neurotoxic NRTIs, such as zalcitabine and stavudine, are able to induce changes in the peripheral and the CNS in rodent models that are associated with hypernociception. However, there are model-specific inconsistencies in precisely how these changes are expressed, depending on the drug and dosing schedule used. This complicates the understanding of how drugs used in the treatment of HIV may cause hypernociception. Combined viral & antiretroviral drug
toxicity
While models of hypernociception induced by antiretroviral drugs are useful for understanding the toxicity of the drugs themselves, these agents are typically used in patients with an underlying HIV infection. Several investigators have therefore studied hypernociception in models combining viral and antiretroviral drug exposure [67,69,76]. Perhaps not unexpectedly, synergistic neurotoxicity has typically been observed. For example, transgenic mice constitutively expressing gp120 (at a level that was not neurotoxic in itself) in all tissues under a GFAP promotor developed thermal hypernociception and reduced intraepidermal nerve fiber density when administered didanosine in their drinking water at a dose that would normally be nonalgogenic and non-neurotoxic to mice [76]. Mechanistically, the hypernociception seen with combined viral and drug exposures appear similar to that seen with either agent alone, but of greater magnitude. For example,
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exposure of the rat sciatic nerve to gp120, together with repeated doses of zalcitabine over a 3-week period, resulted in greater reductions in mechanical paw withdrawal thresholds, enhanced expression of CCL2 in the DRG and greater activation of dorsal horn microglia compared with animals exposed to either gp120 or zalcitabine alone [69]. Inhibiting the microgliosis significantly attenuated the hypernociception, indicating its importance to the hypernociceptive state [69]. In a similar model, employing a single injection of zalcitabine in rats whose sciatic nerve had been exposed to gp120, this combination resulted in increased expression of CCR2, CXCR4 and their respective ligands (CCL2 and CXCL12) in the DRG. Here only blockage of CXCR4, and not CCR2, reduced the mechanical hypernociception [67]. Future needs in the laboratory study of
HIV-SN pain
Overall, inflammatory changes in the DRG and dorsal horn appear central to the development of hypernociception in models examining the pathogenesis of pain secondary to HIV, antiretroviral drugs or both. However, it remains unproven whether or not the algogenic processes described in animal models are active in humans. As set out above, although postmortem data demonstrate inflammatory changes in the peripheral nerve trunk and dorsal root ganglia of individuals infected with HIV, unfortunately no attempt has been made to link these changes to the presence of painful (compared with nonpainful) neuropathy [41,42,59–61]. It is therefore unclear whether inflammation is a major driver of pain or is present in all patients with nerve damage attributable to HIV-SN. Moreover, the
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SPECIAL REPORT Cherry, Wadley & Kamerman post-mortem studies are largely historical and therefore primarily reflect the neuropathological features of patients who had not been exposed to antiretroviral therapy. There is a need to repeat these studies in a modern cohort of patients who were receiving cART. In parallel with these human neuroanatomical studies, we contend that the continued development and optimization of animal models of painful HIV-SN is an important research need. For example, we need modeling of the effects of active viral infection rather than only acute, localized exposure to viral coat proteins. In addition, antiretroviral drugs that are relevant to modern clinical practice must be studied. Animal models provide the primary basis for preclinical testing of analgesics (existing and novel) that may relieve the symptoms of painful HIV-SN, and the current lack of evidence-based analgesic strategies for treating HIV-SN pain makes such testing a clear priority [9]. Painful HIV-SN in the context of current HIV management practices The recognized risk factors for HIV-SN have evolved with rapid changes in the management of HIV infection [3]. Today, HIV treatment guidelines, particularly in well-resourced countries, recommend commencing antiretroviral therapy early in the course of HIV [101]. Additionally, the WHO has recommended that stavudine should be phased out in favor of less toxic antiretroviral agents [102]. Despite this, we expect HIV-SN rates will remain high for the foreseeable future, even among populations who have never used stavudine. Some individuals will present and/or initiate cART late in HIV disease, placing them at potentially preventable high risk. Avoiding stavudine is unlikely to affect any other factors independently associated with SN risk, including factors that are currently poorly understood, such as host genetics. Most importantly, the available, systematically collected SN data from cohorts who have never been exposed to neurotoxic NRTIs confirm high rates of neuropathy [1,77]. This contrasts with cART initiation trials reporting incident SN rates during tenofovir-based cART as low as 3% in 48 weeks [78]. However, such studies typically rely on spontaneous reporting of SN symptoms (rather than active SN case ascertainment) and the low rates of HIV-SN observed, even in the stavudine treatment group, suggest true rates of SN may have been underestimated. In the CHARTER cohort, where patients are systematically assessed for symptoms and signs
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of neurological disease, 330 (45%) of 741 patients who had never been exposed to any neurotoxic NRTIs were found to have neuropathic signs consistent with SN and 113 (15%) were affected by painful HIV-SN [1]. Thus the available systematically collected evidence suggests HIV-SN pain will remain a major clinical problem, even in the era of ‘safer’ cART and no currently available pharmaceutical has been shown to provide better analgesia than placebo in a randomized trial in HIV-SN [9,79].This raises the important question of how best to understand, prevent and manage HIV-SN pain in the context of current (and evolving) HIV care. Conclusion & future perspective There can be no doubting the current clinical impact of painful SN among individuals living with HIV. Adults diagnosed with HIV infection now enjoy a near normal life expectancy with access to medical care [80,81], but have particularly limited regenerative capacity in their peripheral nervous system [82]. Therefore, the future of painful HIV-SN is expected to include a large and aging population affected by prevalent SN, together with ongoing incident cases. The size of this latter group cannot yet be predicted accurately, but for the reasons outlined above, we expect a substantial subset of individuals with HIV to be affected. Given the profound negative impact of neuropathic pain on patients’ lives [8], the lack of proven effective analgesic strategies for HIV-SN pain and the many gaps in our understanding of the epidemiology and pathogenesis of painful HIV-SN, more work is urgently needed in at least four areas [9,79]: A more consistent approach to assessing
patients for HIV-SN in epidemiologic studies, ideally using tools validated in this context, is needed. We recommend the AIDS Clinical Trials Group brief peripheral neuropathy screen as an appropriate minimum clinical data collection tool for this purpose. The AIDS Clinical Trials Group brief peripheral neuropathy screen has the advantages of being simple to administer, assessing all of the symptoms, symptom severity and signs, and having been validated in HIV-SN [83]. Where practical, further phenotyping of patients using additional pain descriptors and/or more detailed examination (even modalities such as sensory threshold testing) may be useful (see point four below);
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Painful HIV-associated sensory neuropathy Large-scale epidemiological studies need to
be undertaken in order to better understand the prevalence, incidence rates and associations with painful HIV-SN in the context of current HIV management practices. These must include measures of quality of life and function, and the collection of DNA to allow investigation of genetic risk factors, at least at the level of genome-wide association scans. The identification of potentially avoidable factors associated with incident painful HIV-SN could underpin future prevention strategies; Laboratory work to better understand the
mechanisms of pain in HIV-SN will require optimized models to explore the role of replicating viruses and currently recommended antiretroviral drugs. For example, there have been informative recent reports on primate models of HIV-SN, which have employed active infection of monkeys with simian immunodeficiency virus [84]. The development and testing of novel analgesic strategies will be the logical extension of optimized laboratory models; Clinical trials to test evidence-based prevention
and analgesic strategies for patients with painful HIV-SN are needed. Better phenotyping of patients for inclusion in therapeutic clinical trials may identify particular subgroups likely to benefit from existing analgesics that have not proved effective in unselected populations with HIV-SN pain. References Papers of special note have been highlighted as: of interest of considerable interest n n
1
n n
Ellis R, Rosario D, Clifford D et al. Continued high prevalence and adverse clinical impact of human immunodeficiency virus-associated sensory neuropathy in the era of combination antiretroviral therapy: the CHARTER Study. Arch. Neurol. 67(5), 552–558 (2010). The CHARTER study is providing systematically collected data on neurological diseases among HIV patients currently attending six US treatment centers. This paper describes the only substantial neuropathy data set collected from treated HIV patients never exposed to any neurotoxic nucleoside analog reverse
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Currently, an estimated 34 million people are living with HIV [103]. In Africa, where the burden of disease is greatest, stavudine use remains common, and extraordinarily high prevalence rates of painful HIV-SN are reported [2]. Data on rates of painful HIV-SN in other parts of the world are limited, but the CHARTER study demonstrates a 15% prevalence, even among those who have never used neurotoxic NRTIs. At the most basic level, better documentation of the number and severity of cases is needed to understand the overall impact of painful HIV-SN at a societal level and to guide future health policy. More sophisticated studies will be needed to inform evidence-based prevention and management strategies with the potential to improve the lives of individuals living with HIV. Financial & competing interests disclosure CL Cherry is supported by funding from Australia’s National Health and Medical Research Council and gratefully acknowledges the contribution to this work of the Victorian Operational Infrastructure Support Program received by the Burnet Institute. She has previously received support for HIV-SN related research from CNS Bio Australia, Zymes LLC and Roche Australia. AL Wadley has consulted for Pfizer regarding assessment for HIV-SN. PR Kamerman has received honoraria from Pfizer for educational presentations related to HIV-SN. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the p roduction of this manuscript. transcriptase inhibitors, and demonstrates an ongoing high rate of neuropathic pain in this group (113 out of 741 [15%]).
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Wesselingh S, Price P. Cytokine genotype suggests a role for inflammation in nucleoside analog-associated sensory neuropathy (NRTI-SN) and predicts an individual’s
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57 Wadley A, Lombard Z, Cherry C, Price P,
Kamerman P. Analysis of a previously identified ‘pain protective’ haplotype and individual polymorphisms in the GCH1 gene in Africans with HIV-associated sensory neuropathy: a genetic association study. J. Acquir. Immune Defic. Syndr. 60(1), 20–23 (2012).
Affandi J, Price P, Imran D, Yuhaningsih E, Djauzi S, Cherry C. Can we predict neuropathy risk before stavudine prescription in a resource limited setting? AIDS Res. Hum. Retroviruses 24(10), 1281–1284 (2008).
46 Chew C, Cherry C, Kamarulzaman A, Yien
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B. Assessing negative thoughts in response to pain among people with HIV. Pain 105(1–2), 239–245 (2003).
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Provides a succinct and up-to-date summary of the pathogenesis of HIV-associated sensory neuropathy and the associated neuropathic pain, based on data from in vitro and in vivo experimental models.
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Hammond DL, Miller RJ. Chemokines and glycoprotein120 produce pain hypersensitivity by directly exciting primary nociceptive neurons. J. Neurosci. 21(14), 5027–5035 (2001). 65 Acharjee S, Noorbakhsh F, Stemkowski P
et al. HIV-1 viral protein R causes peripheral nervous system injury associated with in vivo neuropathic pain. FASEB J. 24(11), 4343–4353 (2010). 66 Zheng W, Ouyang H, Zheng X et al. Glial
TNFa in the spinal cord regulates neuropathic pain induced by HIV gp120 application in rats. Mol. Pain 7, 40 (2011). 67 Bhangoo S, Ripsch M, Buchanan D, Miller
R, White F. Increased chemokine signaling in
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Zheng X, Ouyang H, Liu S, Mata M, Fink D, Hao S. TNFa is involved in neuropathic pain induced by nucleoside reverse transcriptase inhibitor in rats. Brain Behav. Immun. 25(8), 1668–1676 (2011).
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Establishment of a rodent model of HIV-associated sensory neuropathy. J. Neurosci. 26(40), 10299–10304 (2006). 77 Cherry C, Affandi J, Brew B et al. Hepatitis C
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A randomized, double-blind, controlled study of NGX-4010, a capsaicin 8% dermal patch, for the treatment of painful HIVassociated distal sensory polyneuropathy. J. Acquir. Immune Defic. Syndr. 59(2), 126–133 (2012).
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SPECIAL REPORT Cherry, Wadley & Kamerman 80 Mills E, Bakanda C, Birungi J et al. Life
expectancy of persons receiving combination antiretroviral therapy in low-income countries: a cohort analysis from Uganda. Ann. Intern. Med. 155(4), 209–216 (2011). 81 van Sighem AI, Gras LA, Reiss P, Brinkman
K, de Wolf F; ATHENA National Observational Cohort Study. Life expectancy of recently diagnosed asymptomatic HIV-infected patients approaches that of uninfected individuals. AIDS 24(10), 1527–1535 (2010). 82 Hahn K, Triolo A, Hauer P, Mcarthur J,
Polydefkis M. Impaired reinnervation in HIV infection following experimental denervation. Neurology 68(16), 1251–1256 (2007).
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Important study demonstrating impaired nerve regeneration following capsaicin ablation in HIV patients compared with controls. Patients with HIV-associated sensory neuropathy had even poorer regenerative capacity than HIV patients without sensory neuropathy.
83 Cherry C, Wesselingh S, Lal L, Mcarthur
J. Evaluation of a clinical screening tool for HIV-associated sensory neuropathies. Neurology 65(11), 1778–1781 (2005). 84 Laast V, Shim B, Johanek L et al.
Macrophage-mediated dorsal root ganglion damage precedes altered nerve conduction in SIV-infected macaques. Am. J. Pathol. 179(5), 2337–2345 (2011).
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(2011). www.who.int/hiv/data/en (Accessed 3 July 2012)
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Painful HIV-associated sensory neuropathy
Practice Points
Catherine Louise Cherry*1,2, Antonia L Wadley2 & Peter R Kamerman2 Sensory neuropathy is a frequent complication of HIV and many affected patients suffer from
neuropathic pain. HIV-associated sensory neuropathy (HIV-SN) risk factors include advanced HIV disease, exposure to
neurotoxic antiretroviral drugs, factors associated with neuropathy risk in any setting (age, height, diabetes and so on) and genetic factors (including genes associated with inflammation). Neuropathic pain is the major driver of morbidity in HIV-SN. The determinants of HIV-SN pain are not well described and evidence-based analgesic options are lacking. Animal models support a role for inflammation in the pain of HIV-SN, whether triggered by viruses,
neurotoxic medication or a combination of both. The available data suggest that painful HIV-SN will remain common, even in cohorts never exposed to
neurotoxic antiretroviral medications. Future research needs to include epidemiologic work and genetic studies (to understand the size of the
problem and associations with HIV-SN pain in the context of modern HIV management), development of optimized laboratory models incorporating active viral replication and currently recommended antiretroviral agents, and clinical trials of both prevention and management strategies for HIV-SN.
SUMMARY Painful HIV-associated sensory neuropathy (HIV-SN) is an early recognized neurological complication of HIV. The introduction of effective HIV treatments saw increased rates of HIV-SN, with some antiretrovirals (notably stavudine) being neurotoxic. Although neurotoxic antiretrovirals are being phased out, the available data suggest that incident HIV-SN will remain common, impairing quality of life, mobility and ability to work. Despite its major clinical importance, the pathogenesis and determinants of pain in HIV-SN are poorly understood, and effective prevention and analgesic strategies are lacking. Here, we review what is known about the rates and risk factors for painful HIV-SN, the laboratory models informing our understanding of neuropathic pain in HIV, and the future clinical and laboratory work needed to fully understand this debilitating condition and provide effective management strategies for those affected. Infectious Diseases Unit, The Alfred Hospital, Centre for Virology, Burnet Institute; and Faculty of Medicine, Nursing & Health Sciences, Monash University, Commercial Road, Melbourne, Victoria 3004, Australia 2 Brain Function Research Group, School of Physiology, Faculty of Health Sciences, University of Witwatersrand, South Africa *Author for correspondence: Tel.: +61 3 9076 2000; Fax: +61 3 9076 2431; [email protected] 1
10.2217/PMT.12.67 © 2012 Future Medicine Ltd
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SPECIAL REPORT Cherry, Wadley & Kamerman Sensory neuropathy (SN) is a common complication of HIV and some HIV treatments [1–4]. Most patients with symptomatic HIV-associated SN (HIV-SN) experience neuropathic pain [1–3,5] with consequent impairment of mood, physical function, quality of life and ability to work [1,6–8]. The morbidity associated with HIV-SN is further magnified by the lack of evidence-based analgesic options for affected patients [9]. The high disease burden and lack of effective treatments makes HIV-SN painful. This is a problem that warrants urgent attention; a better understanding of the pathogenesis of HIV-SN and the painful symptoms of the neuropathy will be critical in designing effective prevention and management strategies. Epidemiology of HIV-SN It is not fully understood why some individuals with HIV develop SN and others with similar exposures do not. However, some epidemiologic factors have been described (reviewed recently in [10], including discussion of the lack of a ‘gold standard’ method for diagnosing HIV-SN that complicates understanding of this topic). In the era before combination antiretroviral therapy (cART) was available, HIV-SN was primarily a complication of advanced HIV. Prevalence rates were low (1.5%) in air force recruits identified to be HIV infected [11]. They rose to around 13% in ambulatory HIV-care clinic populations [12,13] and were highest (35%) among hospitalized patients with AIDS [14]. The association between HIV-SN risk and advanced HIV was prominent, despite some differences in how HIV-SN was defined by various authors. Following the introduction of effective HIV treatments, rates of HIV-SN increased, at least in part, because of the neurotoxicity of some antiretroviral medications (notably the neurotoxic nucleoside analog reverse transcriptase inhibitors [NRTIs] stavudine, didanosine and zalcitabine) [3]. Very high rates of symptomatic HIV-SN (up to 57% [2]) have been described in diverse cohorts since the introduction of cART, with exposure to stavudine – the most widely used of the neurotoxic NRTIs – typically found to be a significant risk factor [2,3,15–21]. It has been widely hypothesized that NRTI side effects, including neuropathy, are attri butable to the mitochondrial toxicity of these drugs [22–26]. Polymorphisms in mitochondrial DNA have been independently associated with
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HIV-SN among patients of European [27,28] and African–American [29] descent. The possible contribution to HIV-SN risk of nuclear DNA polymorphisms that affect mitochondrial function has also been considered. For example, genes involved in iron transport (essential to healthy mitochondrial function) have been associated with increased SN risk in patients exposed to neurotoxic NRTIs [30]. Initial explor ation of polymorphisms in the gene encoding mitochondrial polymerase g found no association between HIV-SN and the number of CAG repeats in one small study [31]. Other polymorphisms in this gene, including some that have been linked to other neurological diseases, have not yet been examined for any association with HIV-SN risk and warrant investigation [32]. In addition, hypothesis-free genome-wide studies (rather than only hypothesis-driven candidate gene studies) would inform our understanding of both the mechanisms and risk factors for HIV-SN. Factors that increase risk of peripheral neuro pathy in other settings have generally also been associated with HIV-SN risk, independent of whether or not the patient has been exposed to neurotoxic NRTIs. For example, increasing age is one of the most consistently observed risk factors for SN among people living with HIV [2,3,18,33,34]. Similarly, increasing height [2,18], the presence of diabetes mellitus [34,35] and exposure to isoniazid [5,17,20] have all been found to associate with HIV-SN. A range of other associations with HIV-SN risk are also described. Consistent with HIV-SN rates increasing with disease progression among those with untreated HIV, a lower nadir CD4 count has been described as a risk factor for HIV-SN in some cART-treated cohorts [33]. Ethnicity may be important, with studies undertaken in Africa typically finding higher HIV-SN prevalence rates than those performed elsewhere [10]. We find, using identical methods at sites in five countries, that symptomatic HIV-SN prevalence is increased among black people (data currently published in abstract form) [36]. However, when SN has been defined on the basis of neuropathic signs alone, increased risk has not been consistently associated with a particular ethnic group [15,34,37]. It is possible that antiretroviral medications (other than the neurotoxic NRTIs) may increase HIV-SN risk, notably protease inhibitors [3,38,39], although this also remains controversial [15,40].
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Painful HIV-associated sensory neuropathy Several pieces of evidence point to a likely role for the host inflammatory response in HIV-SN risk, whether triggered by HIV itself, HIV treatments or a combination of both. Firstly, accumulation of activated macrophages in the nervous system has been documented in all neurological diseases associated with untreated HIV and can occur despite advanced immune suppression [41,42]. Increased levels of TNF-a and reduced levels of IL-4 were also documented in peripheral nerves from six patients with HIV-SN, but not neuropathy-free individuals with HIV [43]. HIV-SN occurring in the context of antiretroviral therapy is clinically similar to that seen in untreated HIV, suggesting possible shared mechanisms. Consistent with this, cytokine genot ype (notably alleles of TNFA), has been associated with HIV-SN in stavudine-treated patients and changes in chemokine levels with cART initiation may be predictive of HIV-SN [44–46]. Epidemiology of painful HIV-SN The majority of patients with symptomatic HIV-SN experience pain [1–3,5]. Despite this, there has been relatively little work done to understand the epidemiology of painful HIV-SN; a particularly surprising evidence gap considering the central importance of neuropathic pain to the burden of disease [47]. The negative impact of HIV-SN pain on the lives of patients was highlighted in a 2010 publication from the US-based CHARTER study. The authors presented HIV-SN prevalence data from a cohort of 1539 adults with HIV attending six hospital-based HIV care clinics [1]. Of 536 patients found to have symptomatic SN, 335 (62.5%) had neuropathic pain. In this cohort, neuropathic pain was independently associated with unemployment (odds ratio: 1.58, 95% CI: 1.18–2.11), dependence in activities of daily living (odds ratio: 2.29, 95% CI: 1.72–3.04), reduced quality of life and current evidence of a major depressive disorder (odds ratio: 1.95, 95% CI: 1.45–2.6). More severe pain was associated with a greater likelihood of being unemployed, more frequent dependence and poorer quality of life [1]. Another recent US-based study has confirmed that the severity of neuropathic pain in HIV-SN correlates independently with each of pain-related disability, depressive symptoms and catastrophizing (a negative emotional and cognitive response to pain characterized by magnification [belief that things are worse than they are], rumination and helplessness) [48].
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SPECIAL REPORT
Maladaptive cognitive processes, including negative self-statements and negative social cognitions, associate with increased pain intensity in HIV-SN, as is true in other painful conditions [49]. Pain is clearly central to the clinical impact of HIV-SN. Several pieces of data suggest that pain in HIV-SN may be a function of the severity of nerve dysfunction and damage. For example, psychophysical testing has demonstrated greater hypoesthesia to non-noxious warm stimuli in patients with painful HIV-SN compared with patients with nonpainful HIV-SN. Only patients with pain were hypersensitive to noxious cold (reduced pain threshold) and noxious static mechanical stimuli (reduced pain threshold and increased pain response to suprathreshold stimuli) [50,51]. Indeed, the degree of pain hypersensitivity to static mechanical stimuli correlated with the intensity of patients’ spontaneous pain [50]. At least three studies have demonstrated an inverse relationship between intraepidermal nerve fiber density at the distal leg (a reliable measure of small diameter nerve die-back [52,53]) and severity of pain in patients with HIV-SN [54–56]. In the CHARTER cohort, increasingly severe neuropathic pain was also associated with increased numbers of abnormal neurological signs [1]. Among the subset of patients with detectable viremia at baseline in the AIDS Clinical Trials Group protocol 291, more severe pain and abnormal sensory testing thresholds both associated with higher plasma HIV viral loads – again, supporting an association between pain and the degree of nerve damage [54]. Although the above evidence points to the severity of nerve injury and dysfunction as a major predictor of pain in HIV-SN, the exact nature of the algogenic processes involved has not been fully resolved. Our own recent work examining a possible role for polymorphisms in the CGH1 gene in HIV-SN pain was negative [57]. Previous genetic studies, while providing indirect evidence of possible pathogenic processes involved in HIV-SN, have not generally reported whether or not the candidate genes considered were associated with pain [27–30,44,58]. Post-mortem studies of neural tissues did not attempt to correlate observed pathologies with the presence and severity of pain during life [41,42,59–61]. Similarly, few epidemiologic studies have addressed the question of whether risk factors for painful HIV-SN are the same as those associated with symptomatic HIV-SN
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SPECIAL REPORT Cherry, Wadley & Kamerman in general. Indeed, the CHARTER study suggests the possibility of epidemiologic associations peculiar to painful HIV-SN, with a higher nadir CD4 T-cell count independently associated with pain among patients with neuropathic signs [1]. Therefore, we must currently look to laboratory models for evidence supporting proposed pathogenic mechanisms for pain in HIV-SN. Mechanisms of pain in HIV-SN The establishment of chronic neuropathic pain involves maladaptive changes in the peripheral and the CNS that produce and maintain a hypersensitive pain state [62]. Laboratory models of HIV-SN demonstrate that both viral particles (including viral coat glycoprotein gp120 and viral accessory protein Vpr) and neurotoxic NRTIs (especially zalcitabine) are able to induce thermal and/or mechanical hypersensitivity, including some of the maladaptive changes demonstrated in other models of neuropathic pain [63]. These in vivo and in vitro data are summarized in Table 1 and described in more detail below. HIV-induced hypernociception
Gp120 and Vpr induced hyperexcitability characterized by increased intracellular calcium and changes in membrane potential in cultured dorsal root ganglion (DRG) cells [64,65]. In the case of gp120, these changes involved activation of CXCR4/CCR5 chemokine receptors on cells, and the majority of responsive cells were capsaicin sensitive. It has been hypothesized that this neuronal hyperexcitability may contribute to development of chronic pain through activitydependent sensitization of nociceptive pathways and/or neuronal loss. In animal models, gp120 and Vpr have been shown to induce sustained algogenic changes in the peripheral nerve trunk, DRG and spinal cord dorsal horn [64–70]. For example, exposure of a segment of the rat sciatic nerve to gp120 was associated with acute macrophage infiltration and inflammatory cytokine secretion at the site of exposure [69,70]. This localized inflammation correlated with secondary die-back of intraepidermal nerve fibers [68] (a clinical feature correlated with pain intensity in HIV-SN [54–56]) and inflammatory changes in the DRG (increased TNF-a and CCL2 secretion, and CCR2 expression on sensory neurons) and dorsal horn of the spinal cord (gliosis and increased TNF-a secretion). These inflammatory changes are characteristic of changes observed in other
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models of neuropathic pain [62], and their importance in the pathogenesis of gp120-induced hypernociception is supported by the ability to reverse tactile nociception with administration of a CCR2 receptor antagonist [67] and reduce it by central blockade of TNF-a [66]. Similar to the changes observed in gp120 models, immunodeficient mice expressing the Vpr transgene (vpr/R AG1(-/-) mice) developed mechanical hypersensitivity, which was associated with increased IFN-a expression in the dorsal horn and nerve trunk, and death of DRG neurons [65]. Thus, viral-mediated inflammatory reactions in peripheral nerves and their sequelae in the DRG and spinal cord are sufficient to drive the development of hypernociception in animal models of painful HIV-SN. Hypernociception induced by
antiretroviral drugs
The algogenic mechanisms of treatment-related hypernociception have mainly been studied in animals administered the highly neurotoxic NRTI zalcitabine, which is no longer used therapeutically [69,71]. Consistent with the known ability of NRTIs to inhibit mitochondrial function, the hypernociception following a single intravenous injection of zalcitabine in rats was associated with mitochondrial-dependent activation of proapoptotic caspase pathways [71,72]. In addition, like the algogenic processes induced by viral particles, zalcitabine administration induced inflammatory changes in the DRG and spinal cord dorsal horn. Zalcitabine administration resulted in Schwanncell activation and macrophage infiltration of the DRG, which was associated either with secretion of pronociceptive chemokines, CCL2 (repeated dosing schedule) [69] or CXCL12 (single administration) [73]. With CXCL12 expression, there was also an increase in expression of its receptor, CXCR4, on DRG neurons. Thus, blocking the receptor suppressed zalcitabine-induced hypernociceptive behavior [73]. The dosing schedule of NRTI to animals (repeated vs single administration) may be critical to their effect on algogenic spinal dorsal horn changes. Thrice-weekly zalcitabine dosing for 3 weeks induced hypernociception in rats that was not associated with significant dorsal horn gliosis and was not prevented by inhibitors of glial activation [69]. Conversely, a single administration of high-dose zalcitabine to rats induced significant astrocytosis and TNF-a expression in the dorsal horn, and hypernociception that
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Painful HIV-associated sensory neuropathy
SPECIAL REPORT
Table 1. Algogenic processes in animal models of HIV-associated sensory neuropathy. Sensory Peripheral nerve fiber axon neuropathy type Virus-related
Drug-related
Dorsal root ganglion
Dorsal horn of the spinal cord
Macrophage infiltration Secretion of inflammatory cytokines (TNF-a and IFN-a) Increased membrane excitability
Schwann-cell activation and macrophage infiltration Secretion of inflammatory cytokines (TNF-a and IFN-a) and chemokines (CCL2) Increased membrane excitability Neuronal loss Activation of caspase-dependent Schwann-cell activation and macrophage infiltration nociceptive pathways secondary Secretion of proinflammatory chemokines (CCL2 and to mitochondrial dysfunction CXCL12) Expression of CCR2 and CXCR4 receptors on dorsal root ganglion neurons Secretion of TNF-a by dorsal root ganglion neurons
Microgliosis and astrocytosis Secretion of TNF-a
Astrocytosis Secretion of TNF-a Secretion of BDNF
Adapted from [63].
could be reversed by blocking TNF-a [74]. Oneoff administration of stavudine to mice induced mechanical hypersensitivity that correlated with expression of BDNF in the dorsal horn [75]. These data show that neurotoxic NRTIs, such as zalcitabine and stavudine, are able to induce changes in the peripheral and the CNS in rodent models that are associated with hypernociception. However, there are model-specific inconsistencies in precisely how these changes are expressed, depending on the drug and dosing schedule used. This complicates the understanding of how drugs used in the treatment of HIV may cause hypernociception. Combined viral & antiretroviral drug
toxicity
While models of hypernociception induced by antiretroviral drugs are useful for understanding the toxicity of the drugs themselves, these agents are typically used in patients with an underlying HIV infection. Several investigators have therefore studied hypernociception in models combining viral and antiretroviral drug exposure [67,69,76]. Perhaps not unexpectedly, synergistic neurotoxicity has typically been observed. For example, transgenic mice constitutively expressing gp120 (at a level that was not neurotoxic in itself) in all tissues under a GFAP promotor developed thermal hypernociception and reduced intraepidermal nerve fiber density when administered didanosine in their drinking water at a dose that would normally be nonalgogenic and non-neurotoxic to mice [76]. Mechanistically, the hypernociception seen with combined viral and drug exposures appear similar to that seen with either agent alone, but of greater magnitude. For example,
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exposure of the rat sciatic nerve to gp120, together with repeated doses of zalcitabine over a 3-week period, resulted in greater reductions in mechanical paw withdrawal thresholds, enhanced expression of CCL2 in the DRG and greater activation of dorsal horn microglia compared with animals exposed to either gp120 or zalcitabine alone [69]. Inhibiting the microgliosis significantly attenuated the hypernociception, indicating its importance to the hypernociceptive state [69]. In a similar model, employing a single injection of zalcitabine in rats whose sciatic nerve had been exposed to gp120, this combination resulted in increased expression of CCR2, CXCR4 and their respective ligands (CCL2 and CXCL12) in the DRG. Here only blockage of CXCR4, and not CCR2, reduced the mechanical hypernociception [67]. Future needs in the laboratory study of
HIV-SN pain
Overall, inflammatory changes in the DRG and dorsal horn appear central to the development of hypernociception in models examining the pathogenesis of pain secondary to HIV, antiretroviral drugs or both. However, it remains unproven whether or not the algogenic processes described in animal models are active in humans. As set out above, although postmortem data demonstrate inflammatory changes in the peripheral nerve trunk and dorsal root ganglia of individuals infected with HIV, unfortunately no attempt has been made to link these changes to the presence of painful (compared with nonpainful) neuropathy [41,42,59–61]. It is therefore unclear whether inflammation is a major driver of pain or is present in all patients with nerve damage attributable to HIV-SN. Moreover, the
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SPECIAL REPORT Cherry, Wadley & Kamerman post-mortem studies are largely historical and therefore primarily reflect the neuropathological features of patients who had not been exposed to antiretroviral therapy. There is a need to repeat these studies in a modern cohort of patients who were receiving cART. In parallel with these human neuroanatomical studies, we contend that the continued development and optimization of animal models of painful HIV-SN is an important research need. For example, we need modeling of the effects of active viral infection rather than only acute, localized exposure to viral coat proteins. In addition, antiretroviral drugs that are relevant to modern clinical practice must be studied. Animal models provide the primary basis for preclinical testing of analgesics (existing and novel) that may relieve the symptoms of painful HIV-SN, and the current lack of evidence-based analgesic strategies for treating HIV-SN pain makes such testing a clear priority [9]. Painful HIV-SN in the context of current HIV management practices The recognized risk factors for HIV-SN have evolved with rapid changes in the management of HIV infection [3]. Today, HIV treatment guidelines, particularly in well-resourced countries, recommend commencing antiretroviral therapy early in the course of HIV [101]. Additionally, the WHO has recommended that stavudine should be phased out in favor of less toxic antiretroviral agents [102]. Despite this, we expect HIV-SN rates will remain high for the foreseeable future, even among populations who have never used stavudine. Some individuals will present and/or initiate cART late in HIV disease, placing them at potentially preventable high risk. Avoiding stavudine is unlikely to affect any other factors independently associated with SN risk, including factors that are currently poorly understood, such as host genetics. Most importantly, the available, systematically collected SN data from cohorts who have never been exposed to neurotoxic NRTIs confirm high rates of neuropathy [1,77]. This contrasts with cART initiation trials reporting incident SN rates during tenofovir-based cART as low as 3% in 48 weeks [78]. However, such studies typically rely on spontaneous reporting of SN symptoms (rather than active SN case ascertainment) and the low rates of HIV-SN observed, even in the stavudine treatment group, suggest true rates of SN may have been underestimated. In the CHARTER cohort, where patients are systematically assessed for symptoms and signs
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of neurological disease, 330 (45%) of 741 patients who had never been exposed to any neurotoxic NRTIs were found to have neuropathic signs consistent with SN and 113 (15%) were affected by painful HIV-SN [1]. Thus the available systematically collected evidence suggests HIV-SN pain will remain a major clinical problem, even in the era of ‘safer’ cART and no currently available pharmaceutical has been shown to provide better analgesia than placebo in a randomized trial in HIV-SN [9,79].This raises the important question of how best to understand, prevent and manage HIV-SN pain in the context of current (and evolving) HIV care. Conclusion & future perspective There can be no doubting the current clinical impact of painful SN among individuals living with HIV. Adults diagnosed with HIV infection now enjoy a near normal life expectancy with access to medical care [80,81], but have particularly limited regenerative capacity in their peripheral nervous system [82]. Therefore, the future of painful HIV-SN is expected to include a large and aging population affected by prevalent SN, together with ongoing incident cases. The size of this latter group cannot yet be predicted accurately, but for the reasons outlined above, we expect a substantial subset of individuals with HIV to be affected. Given the profound negative impact of neuropathic pain on patients’ lives [8], the lack of proven effective analgesic strategies for HIV-SN pain and the many gaps in our understanding of the epidemiology and pathogenesis of painful HIV-SN, more work is urgently needed in at least four areas [9,79]: A more consistent approach to assessing
patients for HIV-SN in epidemiologic studies, ideally using tools validated in this context, is needed. We recommend the AIDS Clinical Trials Group brief peripheral neuropathy screen as an appropriate minimum clinical data collection tool for this purpose. The AIDS Clinical Trials Group brief peripheral neuropathy screen has the advantages of being simple to administer, assessing all of the symptoms, symptom severity and signs, and having been validated in HIV-SN [83]. Where practical, further phenotyping of patients using additional pain descriptors and/or more detailed examination (even modalities such as sensory threshold testing) may be useful (see point four below);
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Painful HIV-associated sensory neuropathy Large-scale epidemiological studies need to
be undertaken in order to better understand the prevalence, incidence rates and associations with painful HIV-SN in the context of current HIV management practices. These must include measures of quality of life and function, and the collection of DNA to allow investigation of genetic risk factors, at least at the level of genome-wide association scans. The identification of potentially avoidable factors associated with incident painful HIV-SN could underpin future prevention strategies; Laboratory work to better understand the
mechanisms of pain in HIV-SN will require optimized models to explore the role of replicating viruses and currently recommended antiretroviral drugs. For example, there have been informative recent reports on primate models of HIV-SN, which have employed active infection of monkeys with simian immunodeficiency virus [84]. The development and testing of novel analgesic strategies will be the logical extension of optimized laboratory models; Clinical trials to test evidence-based prevention
and analgesic strategies for patients with painful HIV-SN are needed. Better phenotyping of patients for inclusion in therapeutic clinical trials may identify particular subgroups likely to benefit from existing analgesics that have not proved effective in unselected populations with HIV-SN pain. References Papers of special note have been highlighted as: of interest of considerable interest n n
1
n n
Ellis R, Rosario D, Clifford D et al. Continued high prevalence and adverse clinical impact of human immunodeficiency virus-associated sensory neuropathy in the era of combination antiretroviral therapy: the CHARTER Study. Arch. Neurol. 67(5), 552–558 (2010). The CHARTER study is providing systematically collected data on neurological diseases among HIV patients currently attending six US treatment centers. This paper describes the only substantial neuropathy data set collected from treated HIV patients never exposed to any neurotoxic nucleoside analog reverse
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Currently, an estimated 34 million people are living with HIV [103]. In Africa, where the burden of disease is greatest, stavudine use remains common, and extraordinarily high prevalence rates of painful HIV-SN are reported [2]. Data on rates of painful HIV-SN in other parts of the world are limited, but the CHARTER study demonstrates a 15% prevalence, even among those who have never used neurotoxic NRTIs. At the most basic level, better documentation of the number and severity of cases is needed to understand the overall impact of painful HIV-SN at a societal level and to guide future health policy. More sophisticated studies will be needed to inform evidence-based prevention and management strategies with the potential to improve the lives of individuals living with HIV. Financial & competing interests disclosure CL Cherry is supported by funding from Australia’s National Health and Medical Research Council and gratefully acknowledges the contribution to this work of the Victorian Operational Infrastructure Support Program received by the Burnet Institute. She has previously received support for HIV-SN related research from CNS Bio Australia, Zymes LLC and Roche Australia. AL Wadley has consulted for Pfizer regarding assessment for HIV-SN. PR Kamerman has received honoraria from Pfizer for educational presentations related to HIV-SN. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the p roduction of this manuscript. transcriptase inhibitors, and demonstrates an ongoing high rate of neuropathic pain in this group (113 out of 741 [15%]).
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