Epidemiology, clinical manifestations, diagnosis, and treatment of HIV-associated distal symmetric polyneuropathy (HIV-DSPN)

INTRODUCTION — Human immunodeficiency virus (HIV) infection is associated with various peripheral nervous system manifestations, the most common of which is distal symmetric polyneuropathy (DSPN) [1].

Peripheral polyneuropathy should be distinguished from other forms of neuropathy, such as mononeuropathies (focal involvement of a single nerve) and polyradiculopathies (involvement of a nerve root). Other less common peripheral nervous system manifestations in HIV include antiretroviral toxic neuropathy (more common with antiretroviral medications that are no longer widely used), acquired inflammatory demyelinating polyradiculoneuropathy, lumbosacral polyradiculopathy, mononeuropathies, autonomic neuropathy, diffuse infiltrative lymphocytosis syndrome, sensory ganglionopathy, and herpes zoster radiculitis. These entities are discussed elsewhere. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis", section on 'Acute inflammatory demyelinating polyneuropathy' and "Polyradiculopathy: Spinal stenosis, infectious, carcinomatous, and inflammatory nerve root syndromes", section on 'Polyradiculopathy in HIV and AIDS'.)

The epidemiology, pathogenesis, clinical manifestations, diagnosis, and management of patients with HIV-associated DSPN (HIV-DSPN) will be reviewed here.

A more generalized approach to a patient with polyneuropathy is discussed separately. (See "Overview of polyneuropathy" and "Approach to the patient with sensory loss".)

EPIDEMIOLOGY

Prevalence — HIV-DSPN is a common neurologic complication in patients with HIV and can interfere with the patient’s activities of daily living. Reported prevalence rates vary from 1 to 69 percent, with a meta-analysis including over 2000 patients demonstrating a pooled prevalence of 38 percent [2,3]. The wide range is likely attributed to the decreasing prevalence of HIV-DSPN over time due to the early use of more effective and less toxic antiretroviral therapy (ART) and the heterogeneity in the patient population between studies (eg, varying degrees of immunosuppression, differences in exposure to certain antiretrovirals, and varying inclusion criteria of symptomatic versus asymptomatic patients).

Risk factors — Before the introduction of effective ART, HIV-DSPN was correlated with advanced HIV (lower CD4 count and a higher viral load) [4,5]. However, in the era of effective ART, most studies have not demonstrated this same correlation [6-9]. Viral load has not been found to be related to HIV-DSPN [8,10-12] and some studies have found a correlation with a higher CD4 count [8-10,13]. In treatment-experienced patients with HIV who have been exposed to older neurotoxic nucleoside reverse transcriptase inhibitors, such as stavudine (d4T), didanosine (ddI), and zalcitabine (ddC), HIV-DSPN can be complicated by a clinically similar peripheral neuropathy syndrome called antiretroviral toxic neuropathy [14]. (See 'Differential Diagnosis' below.)

Other risk factors not related to HIV include older age, diabetes mellitus, triglyceridemia, statin use, substance use, and taller stature [10,12,15-19].

PATHOGENESIS — HIV-DSPN on histopathology is characterized by distal axonal degradation, neuronal loss in the dorsal root ganglia, and reduced intraepidermal nerve fiber density [20-25]. The pathophysiology of HIV-DSPN is not well understood and is likely a combination of direct and indirect toxic effects on the nerves [26].

HIV does not infect cells that lack a CD4 receptor (eg, neurons, dorsal root ganglia, Schwann cells). Virus recovered from nerve tissue is primarily from macrophages and monocytes with relative lack of virus and its infiltrates in the nerve [27]. Therefore, HIV indirectly results in toxic effect through the release of inflammatory cytokines and chemokines from infected monocytes and macrophages [28].

However, HIV likely also exerts a direct toxic effect through the envelope glycoprotein gp120. In vitro studies demonstrate that gp120 can bind to rat dorsal root ganglia (DRG) and activate the complement cascade to lyse neuronal cells [29]. Gp120 binds to perineuronal Schwann cells in the DRG via the CXCR4 receptor. This binding leads to aggregation of the CXCR4 receptor and production of the chemokine, RANTES (regulated upon activation, normal T-cell expressed and secreted), which causes neuronal apoptosis via the production of tumor necrosis factor-a [30]. Gp120 has also been found to activate macrophage infiltration, cause neuronal swelling, induce lysosome exocytosis, and release adenosine triphosphate from Schwann cells, leading to an increase in intracellular calcium and cytosolic reactive oxygen species in DRG neurons [31-33].

Certain genetic factors may also make patients more at risk for HIV-DSPN. A study of mitochondrial deoxyribonucleic acid (DNA) mutations in human axon samples demonstrated higher levels of mitochondrial DNA deletion mutations in sural nerve specimens of patients with HIV-DSPN compared with patients without HIV-DSPN [34]. Mitochondrial haplotype T is found in people of European descent; a unique single nucleotide polymorphism marker for mitochondrial haplotype T (MTND2*LHON4917G) in the gene encoding a subunit of complex I of the mitochondrial electron transport chain was found to be an independent risk factor for HIV-DSPN in patients of European descent who were on ART [35,36].

Abnormalities in regenerative and collateral sprouting are also found in patients with HIV [37].

CLINICAL FEATURES

Clinical symptoms — Research using nerve conduction studies to assess the prevalence of HIV-DSPN suggests that it is asymptomatic in up to 16 percent of individuals [7,38]. When symptoms are present, HIV-DSPN commonly presents with bilateral tingling, numbness, and burning that start distally in the toes and progress proximally. Over time, the tips of the fingers may become affected; this typically occurs when the level of lower extremity sensory symptoms rises to the knees. Degree of proximal progression varies; one study found that 55 percent have symptoms confined to the feet, 34 percent may have symptoms of neuropathy up to the distal leg, and 11 percent have severe neuropathy that rises to the proximal leg [39]. Patients also often report worsening symptoms with skin contact, such as the weight of sheets on the bed [25].

Other symptoms and signs suggestive of HIV-DSPN include imbalance and presence of autonomic dysfunction (eg, dizziness or fainting upon standing, urinary retention or incontinence). Symptoms generally progress gradually over the course of several weeks to months.

Signs of weakness, rapidly progressive symptoms, or asymmetry are uncommon in HIV-DSPN and are suggestive of a different neuropathic disorder. (See 'Differential Diagnosis' below.)

Severity of neuropathy appears to be related to degree of immunosuppression in addition to other factors. In one study, mean vibratory thresholds were higher in patients with acquired immunodeficiency syndrome (AIDS) compared with patients with asymptomatic HIV [40]. In another study of 251 individuals with HIV-DSPN, neuropathy severity on nerve conduction studies correlated with low CD4 counts, older age, abnormal serum albumin, lower hemoglobin levels, and weight loss [1].

Exam features — Neurologic exam demonstrates a reduction in pinprick, light touch, vibration, and temperature sensation in a stocking-glove distribution. Proprioception is typically unaffected, although up to 20 percent have been found to have reduced or absent proprioception on exam [41]. Ankle reflexes may be reduced or absent. Knee reflexes typically remain intact. Both mild distal weakness and muscle cramping in the lower extremities can occur in more severe neuropathy, although true muscle atrophy is rare [1].

Laboratory features — There are no specific laboratory features associated with HIV-DSPN. Cerebrospinal fluid (CSF) analysis is not part of the evaluation of HIV-DSPN and is not associated with specific CSF abnormalities, although CSF pleocytosis can be seen in people with untreated HIV infection.

EVALUATION AND DIAGNOSIS — While HIV-DSPN is a clinical diagnosis, identifying and correcting additional reversible causes of neuropathy (eg, diabetic neuropathy, vitamin B12 deficiency) is warranted to optimize nerve function. DSPN can be multi-factorial and all risk factors should be addressed to reduce symptoms and slow disease progression.

History and examination — The diagnosis of HIV-DSPN should be considered when a patient with HIV presents with distal symmetric neuropathy of the extremities (numbness, tingling, and pain that starts in the feet and may progress proximally). History should include the timing and characteristics of the neuropathy, as well as a review of systems to evaluate for any other potential causes of peripheral neuropathy. Emphasis should be placed on identifying any symptoms and signs of diabetes mellitus, thyroid disorders, kidney and liver disease, connective tissue disorders, and possible nutritional deficiencies (eg, vitamin B12 and folate deficiency). The history should also include potential exposures to various toxins that can induce peripheral neuropathy (eg, heavy alcohol use, medications known to cause neuropathy) as well as a thorough family history to identify any hereditary peripheral neuropathy disorders (table 1). (See "Overview of polyneuropathy", section on 'Etiology and pathogenesis'.)

Examination should be comprehensive to evaluate for other potential causes of peripheral neuropathy, as mentioned above. The neurologic exam should include testing the function of light touch, pin prick sensation, temperature sensation, vibration, and joint position sense to differentiate distal symmetric neuropathy from other types of neuropathy (eg, mononeuropathy, radiculopathy). A more detailed discussion on evaluation of polyneuropathy is found elsewhere. (See 'Differential Diagnosis' below and "Overview of polyneuropathy", section on 'Physical examination'.)

Laboratory testing — There are no laboratory studies that specifically point to HIV-DSPN. The role of laboratory testing is to identify other potential causes of peripheral neuropathy. In most cases, the following studies are recommended in the evaluation of peripheral neuropathy in patients with HIV:

●Blood glucose (preferably fasting)

●Hemoglobin A1C

●Basic metabolic panel

●Serum vitamin B12 and folate levels

●Serum protein electrophoresis with immunofixation, testing of quantitative immunoglobulins, and serum free light chains

●Thyroid stimulating hormone

●Hepatitis B and C antibodies

●Other studies based on risk factors and comorbidities (eg, B. burgdorferi serology in patients living in Lyme-endemic areas, antinuclear antibody panel in patients with personal or family history of autoimmune disorders, heavy metal levels in the blood in patients with poor nutrition or appropriate occupational exposure, evaluation for hereditary polyneuropathies in patients with family history of neurologic disease)

Establishing the diagnosis — In most cases, a typical clinical presentation of a distal sensory neuropathy and exclusion of other causes of peripheral neuropathy in a patient with HIV is sufficient to establish the diagnosis. Occasionally, if the diagnosis is unclear (eg, rapid progression and/or asymmetry of symptoms, presence of weakness), additional testing with nerve conduction study and electromyography may be helpful to further characterize the neuropathy. (See 'Differential Diagnosis' below.)

Additional testing in diagnostic uncertainty — In situations where the diagnosis is uncertain, referral to a neurologist for additional testing is warranted. Additional testing to help establish the diagnosis includes nerve conduction study in conjunction with electromyography, skin biopsy, and nerve biopsy.

●Nerve conduction study and electromyography − When DSPN is not evident from the history and physical exam, a nerve conduction study and electromyography can be helpful to confirm the presence and type of neuropathy. Nerve conduction studies (NCS) typically demonstrate an axonal sensorimotor polyneuropathy. There is a reduction in the amplitude of sensory and motor action potentials in the lower limbs with normal or reduced nerve conduction velocities [1,25,38,42]. Needle electromyography (EMG) study demonstrates an axonal neuropathy with reduced recruitment with polyphasic potentials in distal leg muscles in severe cases [43].

●Skin biopsy − Skin biopsy is typically reserved for patients in whom there is clear evidence of small fiber neuropathy on physical exam and EMG/NCS are negative for large fiber polyneuropathy. Skin biopsy with protein gene product 9.5 immunostaining demonstrates loss of intraepidermal nerve fiber density (IENFD), often before significant large fiber changes are seen on NCS/EMG and has become the gold standard in evaluating small fiber neuropathy [22,44,45]. The degree of reduction of IENFD correlates with the clinical and electrophysiological severity in patients with HIV-DSPN [22]. In a retrospective study of 67 patients with HIV, increased number of large mitochondrial DNA deletions were associated with loss of IENFD and sural nerve amplitude [46].

●Nerve biopsy − Nerve biopsy is usually not necessary in the evaluation of HIV-DSPN. It is usually reserved for patients in whom mononeuritis multiplex is suspected (eg, asymmetric neuropathic symptoms in the distribution of multiple contiguous nerves) and needs to be ruled out. (See 'Differential Diagnosis' below.)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of HIV-DSPN includes other conditions associated with progressive distal symmetric polyneuropathy and other similar neuropathies. These include HIV-antiretroviral toxic neuropathy (HIV-ATN), acute inflammatory demyelinating polyradiculoneuropathy (AIDP), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), progressive radiculopathy, and mononeuritis multiplex. Clinical and neurophysiologic features help distinguish these conditions from HIV-DSPN.

●HIV-antiretroviral toxics neuropathy (HIV-ATN) – HIV-ATN is caused by older nucleoside reverse transcriptase inhibitors such as stavudine (d4T), didanosine (ddI), and zalcitabine (ddC); the presumed mechanism of HIV-ATN is thought to be inhibition of gamma-DNA polymerase, which is required for mitochondrial replication [47,48]. The clinical presentation is similar to that of HIV-DSPN. It can be distinguished from HIV-DSPN by a history of recent exposure to the offending agent, faster onset of symptoms, and symptom resolution with discontinuation of the offending drug [49]. However, a "coasting" phenomenon has also been described, with paradoxical worsening of neuropathic symptoms over a period of four to eight weeks after stopping the offending antiretroviral drug [50,51].

●Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) – AIDP, the demyelinating variant of Guillain-Barré Syndrome, can mimic the clinical features of HIV-DSPN. However, AIDP typically presents with rapidly progressive ascending weakness with areflexia, reaching a nadir within four weeks. Occasionally, it can be a manifestation of HIV seroconversion. NCS/EMG demonstrates a demyelinating neuropathy with slow conduction velocities, prolonged distal latency, and conduction block. (See "Guillain-Barré syndrome in adults: Pathogenesis, clinical features, and diagnosis", section on 'Clinical features'.)

●Chronic inflammatory demyelinating polyradiculopathy (CIDP) – CIDP can present in patients with long-standing HIV infection. It has a more indolent course (symptoms progress for >8 weeks) that can mimic the slow progression of HIV-DSPN. However, CIDP typically presents with ascending weakness while HIV-DSPN presents primarily with sensory deficits. NCS/EMG demonstrates a demyelinating neuropathy with slow conduction velocities, prolonged distal latency, and conduction block. Cerebrospinal fluid (CSF) analysis in patients with HIV and CIDP can demonstrate a mild lymphocytic pleocytosis, although this can also be seen in any patient with HIV. HIV-DSPN is not associated with specific CSF abnormalities [52,53]. CIDP can also be differentiated from HIV-DSPN by its robust response to corticosteroids in patients with HIV, whereas HIV-DSPN does not respond to corticosteroids [54]. (See "Chronic inflammatory demyelinating polyneuropathy: Etiology, clinical features, and diagnosis", section on 'Clinical features'.)

●Progressive polyradiculopathy – Progressive polyradiculopathy in patients with HIV typically presents with rapidly progressive weakness and numbness of the lower extremities with areflexia and sphincter dysfunction. Magnetic resonance imaging of the lumbar spine with gadolinium may demonstrate contrast enhancement of the nerve roots. Since cytomegalovirus (CMV) is a common cause of progressive polyradiculopathy in patients with HIV, CSF CMV DNA by polymerase chain reaction (PCR) is often positive [55,56]. (See "Polyradiculopathy: Spinal stenosis, infectious, carcinomatous, and inflammatory nerve root syndromes", section on 'Polyradiculopathy in HIV and AIDS'.)

●Mononeuritis multiplex – Mononeuritis multiplex in patients with HIV is most commonly caused by CMV infection. This presents with a stepwise, asymmetric weakness and numbness involving two or more peripheral nerves or nerve roots [57-59]. In cases where HIV-DSPN and mononeuritis multiplex cannot be distinguished on clinical presentation and non-invasive tests, nerve biopsy may be necessary. Sural nerve biopsy may demonstrate CD8 lymphocytic infiltration, necrotizing vasculitis, endoneurial infiltrates, and axonal damage [60]. (See "AIDS-related cytomegalovirus neurologic disease" and "Polyradiculopathy: Spinal stenosis, infectious, carcinomatous, and inflammatory nerve root syndromes", section on 'Polyradiculopathy in HIV and AIDS'.)

TREATMENT — The mainstay of treatment is antiretroviral therapy (ART) and pharmacologic and nonpharmacologic therapies for symptom management.

General measures

Correcting reversible risk factors — Patients with HIV-DSPN often have comorbidities that predispose to peripheral neuropathy, including diabetes mellitus, substance use, psychiatric disorders, and other chronic pain disorders [61,62]. Patients with HIV-DSPN are more than twice as likely to have other chronic pain disorders and more likely to have substance use and psychiatric disorders compared with patients with HIV without HIV-DSPN [61]. Identifying and correcting these comorbidities can help alleviate symptoms and prevent further progression. Use of any medications with known neurotoxicity should be minimized (table 1). (See 'Evaluation and diagnosis' above.)

Role of antiviral therapy — ART is recommended for all patients with HIV. It reduces the risk of DSPN and may help to improve painful symptoms and thermal/nociceptive function in patients with neuropathic symptoms [63,64].

In one prospective observational study, 49 patients with HIV (more than half with sensory abnormalities) were initiated on ART and followed for eight months [64]. Patients who had an increase in the CD4 cell count after ART initiation had higher rates of symptom resolution compared with those who did not respond to ART.

Exercise — We encourage all patients who can to exercise regularly. Exercise has wide-ranging health benefits and is a basic component of a healthy lifestyle. Moderate intensity aerobic exercises and progressive-resistance exercises have also demonstrated improvement in quality of life and pain reduction in patients with HIV-DSPN [65,66].

Foot care and fall prevention — We recommend that all patients with neuropathy routinely inspect their feet for any skin fissures, open lesions, and early signs of infection. As more patients with HIV age, prevalence of comorbidities along with the loss of proprioception from HIV-DSPN can lead to worsening balance and increased risk of falls. Clinicians should implement interventions to minimize fall risk and counsel patients on precautions they can take to minimize falls in their daily life. (See "Falls: Prevention in community-dwelling older persons", section on 'Preventing falls'.)

Management of symptoms

Goals of treatment — There are no disease-modifying therapies for HIV-DSPN. The main goal of pharmacotherapy is to maximize symptom control using as few agents as possible with the least amount of side effects. Patients should be counseled that medications can only help reduce the 'positive' symptoms, such as pain and dysesthesias; they have no effect on 'negative' symptoms, such as numbness.

Medications with demonstrated improvement of HIV-DSPN symptoms are scarce. Medications that have demonstrated significant pain reduction in other types of neuropathies, such as diabetic neuropathy, have not demonstrated the same success with HIV-DSPN [67]. This may be due to either different pain mechanisms or to the high placebo response in these studies [68,69].

Access to certain therapies may be limited by cost. In the United States for example, there are no US Food and Drug Administration (FDA)-approved therapies for HIV-DSPN; thus, the agents are used off-label and may not be covered by insurers.

Initial therapy

Considerations in selecting treatment — Gabapentin or pregabalin are our preferred first-line agents for most individuals. Selection between gabapentin and pregabalin is based on drug availability, cost, and provider and patient preference. In some cases, underlying comorbidities may inform drug selection, particularly if second drugs are needed for suboptimal response. As an example, antidepressants that may have beneficial effects on neuropathy (eg, duloxetine or tricyclic antidepressants) may be more appropriate in individuals with comorbid depression. If the patient also has insomnia, agents that have sedating effects, such as gabapentin, pregabalin, or the tricyclic antidepressants, can be useful. However, if there is autonomic dysfunction, tricyclic antidepressants should be avoided (table 2).

Gabapentin or pregabalin for most patients — In patients without depression, we recommend initial therapy with gabapentin. This recommendation is in agreement with the HIV Medicine Association (HIVMA) guidelines for the management of chronic pain in patients living with HIV [70]. Pregabalin is a reasonable alternative if the patient cannot tolerate gabapentin (table 2).

We generally start:

●Gabapentin at 100 to 300 mg one to three times daily and increase the dose weekly until symptoms resolve or we reach the maximum dose of 800 mg three times daily (2400 mg daily in two or three divided doses).

●Pregabalin at 25 to 75 mg two times daily and increase to 75 to 200 mg two times daily if there is no response after several weeks.

Side effects of gabapentin and pregabalin include somnolence, dizziness, ataxia, weight gain, and distal edema.

Gabapentin is the main medication that has demonstrated efficacy in reducing symptoms due to HIV-DSPN. As an example, in a double-blind randomized study of 26 symptomatic patients with HIV-associated sensory neuropathies, gabapentin was more effective in reducing pain and improving sleep compared with placebo (44 versus 30 percent reduction in the median pain score from baseline) [71]. Somnolence was reported in 80 percent of patients who received gabapentin; however, only one patient discontinued gabapentin due to adverse effects.

Patients with depression — In patients with depression, we suggest duloxetine as the initial therapeutic agent as it can help alleviate symptoms of depression in addition to those of HIV-DSPN. Tricyclic antidepressants are an alternative for such patients but are associated with more side effects and should not be used in individuals with autonomic dysfunction. For patients who are taking other antidepressants (eg, selective serotonin reuptake inhibitors), we discuss with the patient about switching to an agent with both antidepressant and analgesic effects (eg, duloxetine) (table 2).

●Duloxetine − Duloxetine should be initiated at 30 to 60 mg daily and can be titrated up to 120 mg daily. Side effects of duloxetine include somnolence, headaches, sexual dysfunction, nausea, vomiting, and hepatocellular hepatitis. Patients should be counseled to take the medication on a full stomach to minimize nausea. Duloxetine should not be combined with other serotonin or norepinephrine reuptake inhibitors (including tricyclic antidepressants) because these combinations can increase the risk of serotonin syndrome.

Data on the efficacy of duloxetine are largely based on its effectiveness in other neuropathic pain syndromes, as studies assessing duloxetine in HIV-DSPN have not shown the same benefit [72,73]. In a randomized study of 15 patients with HIV-DSPN, duloxetine did not demonstrate a significant change in pain intensity compared with placebo [74].

●Tricyclic antidepressants − Tricyclic antidepressants such as amitriptyline or nortriptyline should be started at 10 mg orally at bedtime and titrated up to 75 to 100 mg orally at bedtime. Side effects include dizziness, drowsiness, confusion, constipation, urinary retention, blurred vision, and cardiac arrhythmias.

Data on the efficacy of tricyclic antidepressants are largely based on their effectiveness in other neuropathic pain syndromes, as studies assessing these agents in HIV-DSPN have not shown the same benefit [73]. The tricyclic antidepressants, nortriptyline or amitriptyline, were not found to be more beneficial than placebo in patients with HIV-DSPN [75-77].

Patients who want to avoid systemic medications — Effective options are limited for such patients.

●Topical therapy − The concept of topical therapy is attractive, but options are either difficult to access or do not have demonstrated efficacy.

•Capsaicin patch − The high-concentration (8%) capsaicin dermal patch (NGX-010) is effective, however, challenges with administration limit accessibility. It is applied for 30 minutes every three months (not more frequently) but requires administration in the clinical setting and may require pretreatment with topical lidocaine due to a local burning sensation. In one study, a single, 30-minute application of the high-concentration (8%) capsaicin dermal patch provided 12 weeks of pain reduction compared with low-concentration capsaicin (table 2) [78].

•Lidocaine patch – Lidocaine patch (5%) is used to treat neuropathic pain related to other diseases (eg, diabetic neuropathy). Up to three patches can be applied in a single 24-hour application period, for up to 12 hours. This should be followed up by a patch-free period for at least the next 12 hours. Data on efficacy of lidocaine patches for HIV-DSPN are limited; lidocaine patches have shown modest improvement in pain scores in patients with diabetic neuropathy [79] and postherpetic neuralgia [80].

Other topical agents such as low-dose capsaicin (0.075%) cream and lidocaine gel have not been shown to be effective [81,82].

Reasonable nonpharmacologic options for interested patients include acupuncture, hypnotherapy, and cannabis.

●Acupuncture − The efficacy of acupuncture in reducing symptoms is unclear. In a randomized study of 50 patients with HIV, acupuncture with moxibustion (burning of mugwort leaf) reduced neuropathy symptoms compared with placebo [83]. However, a larger, multicenter randomized study of 250 patients with HIV demonstrated no difference in symptom reduction between acupuncture and placebo [75].

●Hypnotherapy − Hypnotherapy was found to improve quality of life and reduce pain in patients with HIV-DSPN [84].

●Medical and smoked cannabis − Medical or smoked cannabis may be a beneficial treatment in appropriate patients. Since medical cannabis does not have some of the risks of smoked cannabis, it may be a good initial option. For patients interested in smoked cannabis, risks and benefits should be weighed including the harmful effects of smoked cannabis in patients with underlying lung disease, adverse psychoactive effects, and abuse risk. Smoked cannabis was found to be effective in reducing symptoms, improving mood, and improving daily functioning in patients with HIV-DSPN in two randomized trials [85,86].

Follow-up

Assessing response — We generally assess for a response every few weeks during titration of medication dosages and then in one to three months after the patient has been on a stable dose of a therapeutic agent and/or undergone a trial of non-pharmacologic interventions. Additionally, we make sure any reversible risk factors have been corrected prior to assessing response to treatment.

Approach to patients with refractory symptoms

●In individuals with partial response to initial therapy − In a patient who has had a partial response to initial therapy, we suggest the addition of a second agent with a different mechanism of action (table 2).

As an example, for a patient with partial response to gabapentin, we typically add duloxetine; a tricyclic antidepressant is an alternative second agent to add if duloxetine is not well tolerated or cost prohibitive. If duloxetine was initiated as the first agent, gabapentin or pregabalin should be selected as a second agent unless there is a contraindication. Dosing of and support for these medications is discussed elsewhere. (See 'Gabapentin or pregabalin for most patients' above and 'Patients with depression' above.)

●In individuals with no response to initial therapy − In a patient who has had no response to initial therapy, we suggest switching to another agent (table 2).

For patients who cannot take or have limited response to gabapentin, pregabalin, duloxetine, and/or tricyclic antidepressants, lamotrigine is a potentially effective option. Lamotrigine was found to be effective for HIV-DSPN in patients receiving neurotoxic ART, however, further studies in the era of effective ART are needed [87]. We generally administer 200 to 400 mg daily. Lamotrigine should be avoided in patients with heart disease, as it can increase the risk of arrhythmias [88]. Other side effects include dizziness, drowsiness, insomnia, skin rash, nausea, peripheral edema.

Nonsystemic approaches (topical therapies, acupuncture) are potential adjunctive options of variable efficacy. (See 'Patients who want to avoid systemic medications' above.)

Although we do not routinely recommend alpha-lipoic acid (ALA) or acetyl-L-carnitine for HIV-DSPN due to lack of efficacy data and/or the extensive adverse effects associated with the therapy, they may be tried in patients with refractory symptoms or in patients who are intolerant or have contraindications to preferred therapies.

●Alpha lipoic acid − The HIVMA guidelines for the management of chronic pain in patients living with HIV recommends ALA for HIV-DSPN with difficult-to-treat neuropathic pain [70]. This is largely based on literature in diabetic neuropathy, as it has not been assessed in HIV-DSPN. (See "Management of diabetic neuropathy", section on 'Possibly effective'.)

●Acetyl-L-carnitine − Acetyl-L-carnitine, when given intramuscularly, reduced pain ratings when compared with placebo [89]. An open-label single-arm study also improved pain scores, although intraepidermal nerve fiber density (IENFD) was not changed [90].

Limited role of opioid analgesics — Chronic use of opioids should be avoided when possible. Opioids may be considered for breakthrough pain in select cases when patients do not respond to other therapies. We favor tramadol as the opioid of choice in moderate to severe refractory chronic pain when the potential benefits outweigh harm (table 2) [70].

In patients for whom opioids are prescribed for chronic pain, we recommend storing controlled substances away from individuals at risk of misuse and/or overdose, educating patients about avoiding adverse events related to pharmacologic interactions, and educating the patient and family about signs of overdose and use of naloxone to reverse overdose [70]. These recommendations are in line with the HIVMA guidelines for the management of chronic pain in patients living with HIV. (See "Use of opioids in the management of chronic non-cancer pain".)

Pharmacologic agents with unclear benefit — The following agents have not been shown to be more effective than placebo in reducing neuropathic symptoms.

●Neurotrophic agents − A study of recombinant human nerve growth factor demonstrated that it was well tolerated and significantly improved pain symptoms but did not reduce neuropathy severity by neurologic exam, IENFD, or quantitative sensory testing [91]. Another study demonstrated no significant treatment effect on nerve regeneration or collateral sprouting of nerve fibers on punch skin biopsies [92].

●Peptide T − Peptide T demonstrated small success in helping to relieve neuropathic pain in a phase I study [93], although a double-blind, randomized multicenter study showed no significant difference between Peptide T and placebo [94].

●Prosaptide − While safe, prosaptide was ineffective at reducing neuropathic pain in HIV-DSPN [95].

SUMMARY AND RECOMMENDATIONS

●Definition, prevalence, and risk factors − Distal symmetric polyneuropathy (DSPN) is the most common peripheral nervous system manifestation in patients with human immunodeficiency virus (HIV). Risk factors include uncontrolled HIV, older antiretroviral therapy regimens, older age, diabetes mellitus, triglyceridemia, statin use, substance use, and taller stature. (See 'Introduction' above and 'Epidemiology' above.)

●Clinical features

•Clinical symptoms − HIV-associated DSPN (HIV-DSPN) commonly presents with bilateral tingling, numbness, and burning that start distally in the toes and progress proximally. Other symptoms and signs suggestive of HIV-DSPN include imbalance and presence of autonomic dysfunction (eg, dizziness or fainting upon standing, urinary retention or incontinence). Symptoms generally progress gradually over the course of several weeks to months. (See 'Clinical features' above.)

•Exam findings − Neurologic exam findings include a reduction in pinprick, light touch, vibration, and temperature sensation in a stocking-glove distribution, as well as absent or reduced ankle reflexes. (See 'Clinical features' above.)

●Establishing the diagnosis − A typical clinical presentation of a distal sensory neuropathy and exclusion of other causes of peripheral neuropathy (table 1) in a patient with HIV is sufficient to establish the diagnosis. There are no specific laboratory features associated with HIV-DSPN. (See 'Evaluation and diagnosis' above.)

●Differential diagnosis − Differential diagnosis of HIV-DSPN includes HIV-antiretroviral toxic neuropathy, acute inflammatory demyelinating polyradiculoneuropathy, chronic inflammatory demyelinating polyradiculoneuropathy, progressive polyradiculopathy, and mononeuritis multiplex. (See 'Differential Diagnosis' above.)

●Treatment

•General measures – All patients diagnosed with HIV-DSPN should undergo correction or optimization of all reversible risk factors (eg, uncontrolled HIV, diabetes mellitus, vitamin B12 deficiency, substance abuse). Patients should also be counseled to regularly exercise and examine their feet for any skin fissures, open lesions, and early signs of infection. (See 'General measures' above.)

•Initial pharmacologic therapy for symptomatic patients – For symptomatic patients without depression, we suggest gabapentin or pregabalin (Grade 2C), as it has been shown to reduce symptoms. For patients with depression, we suggest duloxetine or tricyclic antidepressants. For patients who are taking other antidepressants (eg, selective serotonin receptor inhibitors), we discuss with the patient about switching to an agent with both antidepressant and analgesic effects (eg, duloxetine) (table 2). (See 'Goals of treatment' above and 'Initial therapy' above and "Management of diabetic neuropathy", section on 'Initial pharmacotherapy'.)

•Alternative therapeutic options – Effective non-pharmacologic options, for those who are interested, include the high-concentration (8%) capsaicin dermal patch (NGX-010), acupuncture, hypnotherapy, and cannabis. (See 'Patients who want to avoid systemic medications' above.)

●Assessing response − We generally assess for a response every few weeks during titration of medication dosages and then one to three months after the patient has been on a stable dose of a therapeutic agent and/or undergone a trial of non-pharmacologic interventions. (See 'Assessing response' above.)

●Refractory symptoms − Management of refractory symptoms includes adding a second agent in those with partial response or switching to an alternative in those with no response (table 2). (See 'Approach to patients with refractory symptoms' above.)