HIV-1-Associated Peripheral Neuropathologies in HIV and Aging (Updated 1/7/18)

  • Distal sensory neuropathy (DSP) is the most common type of peripheral neuropathy in HIV
  • DSP occurs more frequently in older adults living with HIV (PLWH)
  • There are several causes for DSP, including HIV- and non-HIV causes, and determining the cause is key for determining treatment course

HIV-1-ASSOCIATED PERIPHERAL NEUROPATHY is currently one of the most common neuro-AIDS conditions, with about 30-67% of HIV patients experiencing this condition [1, 2].

Distal sensory polyneuropathy (DSP) is the most common type of peripheral neuropathy in the HIV infected. Other types include progressive polyradiculopathy (most commonly occurs with advanced immunosuppression and usually caused by CMV); mononeuropathy multiplex (which occurs in early HIV infection); autonomic neuropathy (which may be caused by central or peripheral nervous system abnormalities); and diffuse infiltrative lymphocytosis syndrome.

DSP Risk Factors and Causes and Symptoms and Risk Factors

About DSP, one type is due to HIV infection itself, and another to antiretroviral (ARV) toxicity, predominantly from the dideoxynucleosides (didanosine and stavudine), and another type may be due to other chronic illnesses such as diabetes. Regarding ARV toxicity of the aforementioned “dD-drugs”, these medications should be avoided in patients at high risk for DSP. Mechanisms of the disease are incompletely understood, with some evidence implicating gp120 mediated neuronal apoptosis for viral-induced DSP and mitochondrial toxicity, with or without DNA polymerase γ involvement, in dideoxynucleoside toxicity-induced DSP [3]. Although most data on DSP and ART has pertained to “d-drugs”, data have also implicated the protease inhibitors [4]. In addition, other medications including dapsone, isoniazid, metronidazole, vincristine, thalidomide, and hydroxyurea all appear to increase the risk of DSP. Other risk factors include greater height [5] , smoking [3], Vitamin B12 deficiency [4] , as well as several comorbidities discussed further below.

Symptoms include pain, numbness or burning, a “pins-and-needles” sensation, shooting pain, and swollen feet. Symptoms typically present as dysesthesias occurring first in the feet and gradually ascend over time. Symptoms infrequently extend to the fingertips and hand and are termed “stocking and glove” distribution. Motor symptoms tend to be minimal. These symptoms typically show a limited response to treatment.

DSP and Older Adults

HIV-associated DSP occurs more frequently in older patients [5]. However, DSP is not as clearly shown to be related to markers of HIV disease progression as was the case in the era prior to effective ART.

While this may seem counterintuitive, it may be that increased longevity and health in patients aging with HIV may allow more time for DSP to develop. Further, in the post HAART era, other non-HIV comorbidities may play a more prominent role in the development of DSP [6, 7]. While there is a current association with age, diagnosis of AIDS, and exposure to neurotoxic ARVs, there is no such association with clinical HIV disease stage, time from diagnosis, current CD4 cell count (across the entire range), or plasma viral load. Aging is independently associated with deterioration of light touch in both the soft and callous skin of the foot [8].

Pain Symptoms

DSP causes significant, ongoing pain, is associated with decreased ARV adherence (threatening control of systemic HIV disease), and has been demonstrated to be a true risk factor for falls in older people [9], including HIV positive persons specifically [10]. It has also been associated with neurocognitive disorders (HAND), as well as unemployment and daily functioning impairments [11].

Isolating the source of neuropathic pain is of concern in older HIV-infected persons living with HIV, who may be suffering from several conditions causing pain and may not be able to distinguish a specific component of neuropathic pain. In fact, the prevalence of pain among HIV-infected persons living with HIV (PLWH) generally had been reported to range from a point prevalence of 54% to one of 83% over a three-month recall period, with moderate-to-severe intensity in one to two and a half different anatomical sites [7].

Older patients diagnosed with DSP should have their pain assessed with standardized pain scales and should receive specific attention to ARV toxicity, maximal pain control, and regular reviews of ARV adherence.

Comorbidities

Several medical and psychiatric comorbidities may increase the likelihood of HIV-associated DSP. Diabetes is capable of substantially raising the risk for DSP. This is a significant clinical concern, given the impact of ARV toxicity-associated insulin resistance and diabetes in the setting of HIV infection. Moreover, ongoing studies have shown an association between high triglyceride levels and DSP.

In addition, patients with HCV co-infection are at risk for DSP, though this comorbidity is more likely in the younger age range. Substance abuse[12] and triglyceridemia have also been shown to be risk factors for DSP, which both may be particularly prevalent in older HIV+ adults. Regarding substance abuse, many clinicians may be hesitant to prescribe these patients’ medications for pain due to concerns of worsening dependence on opioids or suspicion that such patients are seeking pain medications for illicit purposes. Thus, clinicians should be careful in these situations to assess pain symptoms and not undertreat pain[13].

Diagnosis

There is no true gold standard for accurately diagnosing HIV related DSP. Diagnosing DSP in patients with HIVPLWH is important, as isolating the cause of the DSP is key to determining treatment course. Diagnostic testing would be similar to that for any patient with symptoms suggestive of DSP, and should include neurologic exam findings, blood tests and electrodiagnostic testing. Several screening tools exist which incorporate subjective and objective testing-two of which were developed and validated in PLWH. Of course, self-report is the most reliable method to assess pain. Some tools include the Faces Pain Rating Scale and the ACTG Brief Peripheral Neuropathy Scale (BPNS). Others include the Clinical HIV-associated Neuropathy Tool (CHANT). Some scales such as and the Utah Early Neuropathy Score (UENS) have also been studied in PLWH [14].

Treatment

Treatment is of two types, causal and symptomatic. Examples of causal treatment could include avoiding or adjusting neurotoxic medications (including stopping d-drugs if still used as part of ART regimen), adjusting glucose control if diabetes is suspected to be the underlying cause, or if the patient is malnourished.It is important to avoid potential neurotoxic medications.  Deficiencies in vitamins B6, B12 and folate should be corrected.  Thiamine supplementation should be considered. should also be noted that overdosing with B6 supplementation can cause a peripheral neuropathy. There is evidence that the use of statins is associated with a lower risk of a DSP diagnosis [5].  If someone is not on ART, starting treatment and reducing viremia, may also help [15].

Non-pharmacologic therapy

Regarding symptomatic treatment, it is useful to consider non-pharmacological treatments to reduce pain, e.g., advising patients to avoid extended periods of standing or walking, acupuncture [16], biofeedback, hot and cold compresses or baths, wearing looser shoes, soaking their feet in ice water, Patients should be instructed to be aware of an increased risk of falls because of their sensory loss. Therapeutic shoes may also be prescribed. While an invasive approach, neuromodulation of the spinal cord has been suggested as a possible way to treat symptoms of DSP in case studies [17]. Some small studies have also examined the role of medical marijuana in treatment of DSP in PLWH.

Especially in older adults, assessment of balance and fall risk is critical to help compensate help compensate for sensory loss.

Medications Pharmacologic Therapy

Currently there are no FDA approved treatments specifically for HIV DSP. Regarding medications, antidepressants, particularly low doses of amitriptyline, have been used frequently. But, in trials that were well controlled, the antidepressants as a class were always shown to have specific analgesic efficacy for DSP[6, 18, 19]. While amitriptyline has been suggested to be equivalent to nortriptyline in efficacy for neuropathic pain, amtriptyline was specifically not shown to be more effective than placebo in ACTG 242 for HIV-associated DSP[10], suggesting that nortriptyline, may be preferred in the setting of HIV infection. Furthermore, amitriptyline is highly anticholinergic and is an example of a potentially inappropriate medication which should be used with caution in older adults.

There is anecdotal experience  that the specific subgroup of serotonergic and noradrenergic reuptake inhibitor (SNRI) antidepressants (such as venlafaxine and duloxetine) might be more efficacious for pain; however, this cannot be considered to have been empirically confirmed.

Anticonvulsants have also been used, with gabapentin as well as pregabalin being touted for efficacy. A randomized, double-blind, placebo-controlled trial of pregabalin failed to demonstrate significant relief of pain, but hyperalgesia was less pronounced in participants receiving pregabalin compared to placebo [20]. Currently pregabalin has an FDA indication for treatment of DSP, while gabapentin does not. Carbamazepine has been used as well, but represents a risk for drug-drug interactions.

Regarding other drugs for symptomatic treatment, some controlled evidence does show a therapeutic effect for lamotrigine in a small trial followed by a subsequent larger study [12]; however, a meta-analysis reported that lamotrigine was not more effective than placebo.

Lidocaine gel (5%) initially showed promise in an open label study but failed in a controlled clinical trial [14]. A high-dose capsaicin patch has shown controlled evidence for its use in a sample of good size [20]. A trial of the neurotrophic factor prosaptide was terminated based on a planned futility analysis [16]. Acetyl-L-carnitine was unsuccessful as a booster of mitochondrial function in treating HIV-associated DSP in a small open-label study of 20 patients [17] and in a randomized, placebo-controlled trial of 90 patients [21, 22].

Nerve growth factor (NGF) did show improvement of symptoms of HIV-associated DSP in an open-label study of 200 patients [23, 24], but in a randomized placebo-controlled trial of 270 patients it was associated with significant injection-site reactions and is not currently available for clinical use [25, 26]. Memantine [24], mexiletine, and peptide T [27] have been studied with no apparent effect. More recently, the CCR5 antagonist, vicriviroc, was not found to improve pain in a placebo-controlled trial of 118 patients with HIV-associated DSP [28, 29].

Thus, use of the foregoing medications frequently does not achieve a level of pain control that satisfies the patient, and treatment with opioid analgesics (e.g., tramadol, morphine, oxycodone, methadone) can and should be undertaken as necessary. The aim is to maximize pain control and optimize ARV adherence and activities of daily living while minimizing side effects in all patients at need (including those with a history but no current evidence of substance dependence). Use of the WHO Ladder is a generally acknowledged approach that can be effectively supplemented by formal pain contracting and monitoring of efficacy with brief, standardized pain scales (such as the Visual Analogue Scale) and of abuse and diversion with urine toxicology screens.

Updated by Pariya Fazeli PhD

June 2017

References

  1. Benevides ML, Filho SB, Debona R, Bergamaschi EN, Nunes JC. Prevalence of Peripheral Neuropathy and associated factors in HIV-infected patients. J Neurol Sci 2017; 375:316-320.
  2. HHS. Guide for HIV/AIDS Clinical Care – 2014 Edition. U.S. Department of Health and Human Services, Health Resources and Services Administration, Guide for HIV/AIDS Clinical Care – 2014 Edition. . 2014.
  3. Payne BA, Wilson IJ, Hateley CA, Horvath R, Santibanez-Koref M, Samuels DC, et al. Mitochondrial aging is accelerated by anti-retroviral therapy through the clonal expansion of mtDNA mutations. Nat Genet 2011; 43(8):806-810.
  4. Ellis RJ, Marquie-Beck J, Delaney P, Alexander T, Clifford DB, McArthur JC, et al. Human immunodeficiency virus protease inhibitors and risk for peripheral neuropathy. Ann Neurol 2008; 64(5):566-572.
  5. Chen H, Clifford DB, Deng L, Wu K, Lee AJ, Bosch RJ, et al. Peripheral neuropathy in ART-experienced patients: prevalence and risk factors. J Neurovirol 2013; 19(6):557-564.
  6. Goodkin K, Vrancken MAE, Feaster D. On the putative efficacy of the antidepressants in chronic, benign pain syndromes. Pain Forum 1995; 4(4):237-247.
  7. Parker R, Stein DJ, Jelsma J. Pain in people living with HIV/AIDS: a systematic review. J Int AIDS Soc 2014; 17:18719.
  8. Mitchell PD, Mitchell TN. The age-dependent deterioration in light touch sensation on the plantar aspect of the foot in a rural community in India: implications when screening for sensory impairment. Leprosy review 2000; 71(2):169-178.
  9. Munhoz CD, et al. Peripheral neuropathy: a true risk factor for falls. Journal of Gerontological Series A 1995.
  10. Kieburtz K, Simpson D, Yiannoutsos C, Max MB, Hall CD, Ellis RJ, et al. A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection. AIDS Clinical Trial Group 242 Protocol Team. Neurology 1998; 51(6):1682-1688.
  11. Fellows RP, Byrd DA, Elliott K, Robinson-Papp J, Mindt MR, Morgello S, et al. Distal sensory polyneuropathy is associated with neuropsychological test performance among persons with HIV. J Int Neuropsychol Soc 2012; 18(5):898-907.
  12. Simpson DM, McArthur JC, Olney R, Clifford D, So Y, Ross D, et al. Lamotrigine for HIV-associated painful sensory neuropathies: a placebo-controlled trial. Neurology 2003; 60(9):1508-1514.
  13. Ellis RJ, Rosario D, Clifford DB, McArthur JC, Simpson D, Alexander T, 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 2010; 67(5):552-558.
  14. Estanislao L, Carter K, McArthur J, Olney R, Simpson D, Lidoderm HIVNG. A randomized controlled trial of 5% lidocaine gel for HIV-associated distal symmetric polyneuropathy. J Acquir Immune Defic Syndr 2004; 37(5):1584-1586.
  15. Martin C, Solders G, Sonnerborg A, Hansson P. Antiretroviral therapy may improve sensory function in HIV-infected patients: a pilot study. Neurology 2000; 54(11):2120-2127.
  16. Evans SR, Simpson DM, Kitch DW, King A, Clifford DB, Cohen BA, et al. A randomized trial evaluating Prosaptide for HIV-associated sensory neuropathies: use of an electronic diary to record neuropathic pain. PLoS One 2007; 2(6):e551.
  17. Hart AM, Wilson AD, Montovani C, Smith C, Johnson M, Terenghi G, et al. Acetyl-l-carnitine: a pathogenesis based treatment for HIV-associated antiretroviral toxic neuropathy. AIDS 2004; 18(11):1549-1560.
  18. Goodkin K, Feaster DJ, Baldewicz T. Meta-analysis: A time for closer scrutiny in applications to pain research? Pain Forum 1998; 7(2):100-103.
  19. Goodkin K, Gullion CM. Antidepressants for the relief of chronic pain: Do they work? Annals of Behavioral Medicine 1989; 11:83-101.
  20. Simpson DM, Brown S, Tobias J, Group N-CS. Controlled trial of high-concentration capsaicin patch for treatment of painful HIV neuropathy. Neurology 2008; 70(24):2305-2313.
  21. Youle M. Acetyl-L-carnitine in HIV-associated antiretroviral toxic neuropathy. CNS Drugs 2007; 21 Suppl 1:25-30; discussion 45-26.
  22. Youle M, Osio M, Group AS. A double-blind, parallel-group, placebo-controlled, multicentre study of acetyl L-carnitine in the symptomatic treatment of antiretroviral toxic neuropathy in patients with HIV-1 infection. HIV Med 2007; 8(4):241-250.
  23. Schifitto G, Yiannoutsos C, Simpson DM, Adornato BT, Singer EJ, Hollander H, et al. Long-term treatment with recombinant nerve growth factor for HIV-associated sensory neuropathy. Neurology 2001; 57(7):1313-1316.
  24. Schifitto G, Yiannoutsos CT, Simpson DM, Marra CM, Singer EJ, Kolson DL, et al. A placebo-controlled study of memantine for the treatment of human immunodeficiency virus-associated sensory neuropathy. J Neurovirol 2006; 12(4):328-331.
  25. Quasthoff S, Hartung HP. [Nerve growth factor (NGF) in treatment of diabetic polyneuropathy. One hope less?]. Nervenarzt 2001; 72(6):456-459.
  26. Rukwied R, Mayer A, Kluschina O, Obreja O, Schley M, Schmelz M. NGF induces non-inflammatory localized and lasting mechanical and thermal hypersensitivity in human skin. Pain 2010; 148(3):407-413.
  27. Simpson DM, Olney R, McArthur JC, Khan A, Godbold J, Ebel-Frommer K. A placebo-controlled trial of lamotrigine for painful HIV-associated neuropathy. Neurology 2000; 54(11):2115-2119.
  28. Hahn K, Husstedt IW, Arendt GfdDN-A-A. [HIV-associated neuropathies]. Nervenarzt 2010; 81(4):409-417.
  29. Hahn K, Robinson B, Anderson C, Li W, Pardo CA, Morgello S, et al. Differential effects of HIV infected macrophages on dorsal root ganglia neurons and axons. Exp Neurol 2008; 210(1):30-40.
Facebooktwittergoogle_pluslinkedinmail

General Disclaimer: HIV-Age.org is designed for educational purposes only and is not engaged in rendering medical advice or professional services. The information provided through HIV-Age.org should not be used for diagnosing or treating a health problem or a disease. It is not a substitute for professional care. If you have or suspect you may have a health problem, consult your health care provider.