- 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 . Although most data on DSP and ART has pertained to “d-drugs”, data have also implicated the protease inhibitors . 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  , smoking , Vitamin B12 deficiency  , 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 . 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 .
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 , including HIV positive persons specifically . It has also been associated with neurocognitive disorders (HAND), as well as unemployment and daily functioning impairments .
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 .
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.
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 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.
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 .
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 . If someone is not on ART, starting treatment and reducing viremia, may also help .
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 , 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 . 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, 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 . 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 ; 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 . A high-dose capsaicin patch has shown controlled evidence for its use in a sample of good size . A trial of the neurotrophic factor prosaptide was terminated based on a planned futility analysis . 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  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 , mexiletine, and peptide T  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
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