Abstract
HIV-associated sensory neuropathy (HIV-SN) is a common complication of HIV and remains highly prevalent even with modern HIV management strategies, causing debilitating pain in millions globally. We review HIV-SN diagnosis and management. We suggest most HIV-SN cases are easily recognized using clinical screening tools, with physician assessment and/or specialized testing prioritized for atypical cases. Management aims to prevent further nerve damage and optimize symptom control. Symptom relief is difficult and rarely complete, with a lack of proven pharmacological strategies. Work is needed to clarify optimal use of available medications. This includes understanding the marked placebo effect in HIV-SN analgesic trials and exploring ‘responder phenotypes’. Limited data support nondrug strategies including hypnosis, meditation, psychology, physical activity and a positive therapeutic relationship.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 . Inflammatory neuropathy in homosexual men with lymphadenopathy. Neurology 35(10), 1479–1483 (1985).
- 2 . HIV-associated sensory neuropathy: still a problem in the post-stavudine era? Future Virol. 7(9), 848–854 (2012).
- 3 Hepatitis C seropositivity is not a risk factor for sensory neuropathy among patients with HIV. Neurology 74(19), 1538–1542 (2010).
- 4 Prevalence of and risk factors for HIV-associated neuropathy in Melbourne, Australia 1993–2006. HIV Med. 8(6), 367–373 (2007).
- 5 . HIV neuropathy risk factors and symptom characterization in stavudine-exposed South Africans. J. Pain Symptom Manage. 41(4), 700–706 (2011).
- 6 Neurologic disorders are prevalent in HIV-positive outpatients in the Asia-Pacific region. Neurology 71(1), 50–56 (2008).
- 7 HIV neuropathy in South Africans: frequency, characteristics, and risk factors. Muscle Nerve 41(5), 599–606 (2010).
- 8 . Assessment of the prevalence of distal symmetrical polyneuropathy and its risk factors among HAART-treated and untreated HIV infected individuals. Ethiop. Med. J. 48(2), 85–93 (2010).
- 9 Age and height predict neuropathy risk in patients with HIV prescribed stavudine. Neurology 73(4), 315–320 (2009).
- 10 . Maintaining wellbeing for South Africans receiving ART: the burden of pain and symptoms is greater with longer ART exposure. S. Afr. Med. J. 104(2), 119–123 (2014).
- 11 Sensory, psychological, and metabolic dysfunction in HIV-associated peripheral neuropathy: a cross-sectional deep profiling study. Pain 155(9), 1846–1860 (2014).
- 12 Burden of HIV-related neuropathic Pain in the United States. J. Int. Assoc. Provid. AIDS Care
doi:10.1177/2325957415592474 (2015) (Epub ahead of print). - 13 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). •• Perhaps the most convincing epidemiologic data demonstrating the continuing high prevalence of HIV-associated sensory neuropathy (HIV-SN) in populations never exposed to known neurotoxic antiretroviral medications.
- 14 . Pharmacological treatment of painful HIV-associated sensory neuropathy: a systematic review and meta-analysis of randomised controlled trials. PLoS ONE 5(12), e14433 (2010). • A systematic review of randomized analgesic trials for HIV-SN.
- 15 Global Health Observatory Data, HIV/AIDS. www.who.int/gho/hiv/en/.
- 16 . Neurologic complications and considerations in HIV-infected persons. Curr. Infect. Dis. Rep. 15(1), 61–66 (2013).
- 17 HIV peripheral neuropathy progression: protection with glucose-lowering drugs? J. Neurovirol. 18(5), 428–433 (2012).
- 18 . Evaluation of a clinical screening tool for HIV-associated sensory neuropathies. Neurology 65(11), 1778–1781 (2005).
- 19 . Evaluating the diagnostic capacity of a single-question neuropathy screen (SQNS) in HIV positive Zambian adults. J. Neurol. Neurosurg. Psychiatry 81(12), 1380–1381 (2010).
- 20 Association of self-reported painful symptoms with clinical and neurophysiologic signs in HIV-associated sensory neuropathy. Pain 151(3), 732–736 (2010).
- 21 Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology 70(18), 1630–1635 (2008).
- 22 . Current perspectives on HIV-related pain and its management: insights from sub-Saharan Africa. Pain Manag. 1(6), 587–596 (2011).
- 23 . Comorbidity of restless legs syndrome and HIV infection. J. Neurol. 254(10), 1401–1406 (2007).
- 24 . HIV-associated sensory neuropathies. AIDS 16(16), 2105–2117 (2002).
- 25 . Peripheral nerve function in HIV infection: clinical, electrophysiologic, and laboratory findings. Arch. Neurol. 56(1), 84–89 (1999).
- 26 . Painful and painless peripheral sensory neuropathies due to HIV infection: a comparison using quantitative sensory evaluation. Pain 80(1–2), 265–272 (1999).
- 27 . Thermosensory threshold: a sensitive test of HIV associated peripheral neuropathy? J. Neurovirol. 4(4), 433–437 (1998).
- 28 . Intraepidermal nerve fiber density in patients with painful sensory neuropathy. Neurology 48(3), 708–711 (1997).
- 29 . Epidermal nerve fiber density: normative reference range and diagnostic efficiency. Arch. Neurol. 55(12), 1513–1520 (1998).
- 30 Cutaneous innervation in sensory neuropathies: evaluation by skin biopsy. Neurology 45(10), 1848–1855 (1995).
- 31 Antiretroviral use and other risks for HIV-associated neuropathies in an international cohort. Neurology 66(6), 867–873 (2006).
- 32 Correlates of epidermal nerve fiber densities in HIV-associated distal sensory polyneuropathy. Neurology 68(24), 2113–2119 (2007).
- 33 Early detection of subclinical HIV sensory polyneuropathy using intraepidermal nerve fibre density quantification: association with HIV stage and surrogate markers. Int. J. STD AIDS 18(12), 856–860 (2007).
- 34 Determinants of epidermal nerve fibre density in antiretroviral-naive HIV-infected individuals. HIV Med. 13(10), 602–608 (2012).
- 35 Ethnic differences in epidermal nerve fiber density. Muscle Nerve 48(3), 462–464 (2013).
- 36 . Training needs and evaluation of a neuro-HIV training module for non-physician healthcare workers in western Kenya. J. Neurol. Sci. 307(1–2), 92–96 (2011).
- 37 A Phase II trial of nerve growth factor for sensory neuropathy associated with HIV infection. AIDS Clinical Trials Group Team 291. Neurology 54(5), 1080–1088 (2000).
- 38 Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 14(2), 162–173 (2015). •• A useful summary of the data (and its limitations) relating to pharmacologic treatment of neuropathic pain in general.
- 39 Cannabis in painful HIV-associated sensory neuropathy: a randomized placebo-controlled trial. Neurology 68(7), 515–521 (2007).
- 40 Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology 34(3), 672–680 (2009).
- 41 A randomized, double-blind, controlled study of NGX-4010, a capsaicin 8% dermal patch, for the treatment of painful HIV-associated distal sensory polyneuropathy. J. Acquir. Immune Defic. Syndr. 59(2), 126–133 (2012).
- 42 . Topical capsaicin (high concentration) for chronic neuropathic pain in adults. Cochrane Database Syst. Rev. 2, CD007393 (2013).
- 43 . Randomized, double-blind, crossover trial of amitriptyline for analgesia in painful HIV-associated sensory neuropathy. PLoS ONE 10(5), e0126297 (2015).
- 44 Acupuncture and amitriptyline for pain due to HIV-related peripheral neuropathy: a randomized controlled trial. Terry Beirn Community Programs for Clinical Research on AIDS. JAMA 280(18), 1590–1595 (1998).
- 45 A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection. AIDS Clinical Trial Group 242 Protocol Team. Neurology 51(6), 1682–1688 (1998).
- 46 A placebo-controlled trial of gabapentin for painful HIV-associated sensory neuropathies. J. Neurol. 251(10), 1260–1266 (2004).
- 47 A randomized, double-blind, placebo-controlled trial and open-label extension study to evaluate the efficacy and safety of pregabalin in the treatment of neuropathic pain associated with human immunodeficiency virus neuropathy. Pain 155(10), 1943–1954 (2014).
- 48 Pregabalin for painful HIV neuropathy: a randomized, double-blind, placebo-controlled trial. Neurology 74(5), 413–420 (2010).
- 49 Lamotrigine for HIV-associated painful sensory neuropathies: a placebo-controlled trial. Neurology 60(9), 1508–1514 (2003).
- 50 . A placebo-controlled trial of lamotrigine for painful HIV-associated neuropathy. Neurology 54(11), 2115–2119 (2000).
- 51 Experience and challenges presented by a multicenter crossover study of combination analgesic therapy for the treatment of painful HIV-associated polyneuropathies. Pain Med. 14(7), 1039–1047 (2013).
- 52 World Health Organization essential medicines lists: where are the drugs to treat neuropathic pain? Pain 156(5), 793–797 (2015).
- 53 . Placebo response changes depending on the neuropathic pain syndrome: results of a systematic review and meta-analysis. Pain Med. 13(4), 575–595 (2012). •• This paper analyses the placebo response in analgesic trials in different neuropathic pain states, including HIV-SN.
- 54 Increasing placebo responses over time in U.S. clinical trials of neuropathic pain. Pain
doi:10.1097/j.pain.0000000000000333 (2015) (Epub ahead of print). • An interesting and current analysis of how increasing placebo responses, primarily in the USA, may be impacting neuropathic pain trials. - 55 Assessing symptom profiles in neuropathic pain clinical trials: can it improve outcome? Eur. J. Pain 15(5), 441–443 (2011).
- 56 . Subgrouping of patients with neuropathic pain according to pain-related sensory abnormalities: a first step to a stratified treatment approach. Lancet Neurol. 11(11), 999–1005 (2012).
- 57 . Sensory profiles of patients with neuropathic pain based on the neuropathic pain symptoms and signs. Pain 155(2), 367–376 (2014).
- 58 Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): somatosensory abnormalities in 1236 patients with different neuropathic pain syndromes. Pain 150(3), 439–450 (2010).
- 59 . Botulinum toxin type A induces direct analgesic effects in chronic neuropathic pain. Ann. Neurol. 64(3), 274–283 (2008).
- 60 . Systemic lidocaine in pain due to peripheral nerve injury and predictors of response. Neurology 62(2), 218–225 (2004).
- 61 . What can we learn from failed neuropathic pain trials? Neurology 70(4), 250–251 (2008).
- 62 . Pharmacological treatment of painful HIV-associated sensory neuropathy. S. Afr. Med. J. 105(9), 769–772 (2015).
- 63 . Hypnosis for treatment of HIV neuropathic pain: a preliminary report. Pain Med. 14(7), 1048–1056 (2013). • This small pilot study provides the clearest published evidence for the possible efficacy of nondrug strategies for managing HIV-SN pain.
- 64 . Hypnosis for the control of HIV/AIDS-related pain. Int. J. Clin. Exp. Hypn. 50(2), 170–188 (2002).
- 65 Effectiveness of mindfulness-based cognitive therapy on the quality of life, emotional status, and CD4 cell count of patients aging with HIV infection. AIDS Behav. 18(4), 676–685 (2014).
- 66 . Mindfulness-based stress reduction for people living with HIV/AIDS: preliminary review of intervention trial methodologies and findings. Health Psychol. Rev. 9(2), 224–243 (2015).
- 67 Randomized controlled trial of mindfulness-based stress reduction delivered to human immunodeficiency virus-positive patients in Iran: effects on CD4+ T lymphocyte count and medical and psychological symptoms. Psychosom. Med. 74(6), 620–627 (2012).
- 68 Mindfulness meditation in older adults with postherpetic neuralgia: a randomized controlled pilot study. Geriatr. Nurs. 36(2), 154–160 (2015).
- 69 Symptom management and self-care for peripheral neuropathy in HIV/AIDS. AIDS Care 19(2), 179–189 (2007).
- 70 Pain and physical and psychological symptoms in ambulatory HIV patients in the current treatment era. J. Pain Symptom Manage. 43(3), 638–645 (2012).
- 71 . Relationship of depression and catastrophizing to pain, disability, and medication adherence in patients with HIV-associated sensory neuropathy. AIDS Care 23(8), 921–928 (2011).
- 72 Health-related quality of life ‘well-being’ in HIV distal neuropathic pain is more strongly associated with depression severity than with pain intensity. Psychosomatics 53(4), 380–386 (2012).
- 73 Outcomes associated with a cognitive–behavioral chronic pain management program implemented in three public HIV primary care clinics. J. Behav. Health Serv. Res. 39(2), 158–173 (2012).
- 74 . Pain anxiety, acceptance, and outcomes among individuals with HIV and chronic pain: a preliminary investigation. Behav. Res. Ther. 50(1), 72–78 (2012).
- 75 Unhealthy behaviours for self-management of HIV-related peripheral neuropathy. AIDS Care 19(10), 1266–1273 (2007).
- 76 Prevalence, self-care behaviors, and self-care activities for peripheral neuropathy symptoms of HIV/AIDS. Nurs. Health Sci. 12(1), 119–126 (2010).
- 77 . Pain self-management in HIV-infected individuals with chronic pain: a qualitative study. Pain Med. 16(4), 706–714 (2015).
- 78 . A six-month, supervised, aerobic and resistance exercise program improves self-efficacy in people with human immunodeficiency virus: a randomised controlled trial. Aust. J. Physiother. 52(3), 185–190 (2006).
- 79 . Aerobic exercise training for depressive symptom management in adults living with HIV infection. J. Assoc. Nurses AIDS Care 14(2), 30–40 (2003).
- 80 . Aerobic exercise interventions for adults living with HIV/AIDS. Cochrane Database Syst. Rev. (8), CD001796 (2010).
- 81 . Managing pain in women living with HIV/AIDS: a randomised controlled trial testing the effect of a six-week peer-led exercise and education intervention. J. Nerv. Ment. Dis. (2016) (In Press).
- 82 . Progression of pain in ambulatory HIV-positive South Africans. Pain Manag. Nurs. 16(1), e1–e8 (2015).
- 83 Components of placebo effect: randomised controlled trial in patients with irritable bowel syndrome. BMJ 336(7651), 999–1003 (2008).
- 84 . The therapeutic alliance between clinicians and patients predicts outcome in chronic low back pain. Phys. Ther. 93(4), 470–478 (2013).
- 85 Positive provider interactions, adherence self-efficacy, and adherence to antiretroviral medications among HIV-infected adults: a mediation model. AIDS Patient Care STDS 20(4), 258–268 (2006).
- 86 Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection. N. Engl. J. Med. 373(9), 795–807 (2015).
- 87 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach. http://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf.
- 88 . Life expectancy of recently diagnosed asymptomatic HIV-infected patients approaches that of uninfected individuals. AIDS 24(10), 1527–1535 (2010).
- 89 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).
- 90 . HIV-associated sensory neuropathy: risk factors and genetics. Curr. Pain Headache Rep. 16(3), 226–236 (2012). •• A recent review of what is known about risk factors that predispose an individual to developing HIV-SN.
- 91 . Pathogenesis of HIV-associated sensory neuropathy: evidence from in vivo and in vitro experimental models. J. Peripher. Nerv. Syst. 17(1), 19–31 (2012).

