for Health Care Providers
Note: Some medications mentioned in this chapter may not be available on the VHA National Formulary. Consult VA pharmacists for alternatives.
- HIV-associated peripheral sensory neuropathy (HIV-SN) includes distal sensory polyneuropathy (DSP) and ARV toxic neuropathy.
- Patients typically present with bilateral tingling, numbness, or neuropathic pain starting in their toes and spreading proximally; the pain frequently is described as burning or aching and is worse on the soles.
- Patients frequently have impaired sensation and vibratory sense without pain.
- For a very simple and brief evaluation: Ask about distal numbness and check ankle reflexes. Screening for numbness and delayed or absent ankle reflexes has the highest sensitivity and specificity among the clinical evaluation tools.
- Treat suspected ARV toxic neuropathy by withdrawing the offending drug, if possible.
- Treat the pain of HIV-SN with analgesics, anticonvulsants, and topical medication; if severe, treat with long-acting narcotics.
- HIV-SN is a "dying-back" neuropathy, affecting the most distal fibers first, involving myelinated and unmyelinated axons of all sizes. On pathologic examination, this pattern of loss is indistinguishable from other toxic neuropathies.
- Patients typically present with bilateral tingling, numbness, or neuropathic pain that starts in the toes and spreads proximally; the pain frequently is described as burning or aching and is worse on the soles. It also may be described as shocklike or knifelike.
- HIV-SN includes:
- DSP caused by HIV infection itself
- ARV toxic neuropathy resulting from exposure to ARVs, particularly d4T, ddI, and ddC (the "dNRTIs" or "d-drugs"). The onset can occur as early as 9 weeks after starting the offending agent.
- DSP is thought to be related to chronic immune activation, leading to macrophage overproduction of proinflammatory cytokines and chemokines in the peripheral nervous system.
- ARV toxic neuropathy is thought to be associated with mitochondrial toxicities of the dNRTIs.
- Many other drugs and conditions may cause peripheral neuropathy (PN) or compound the condition.
Veterans with HIV*
Peripheral neuropathy: 19%
- A recent study showed the prevalence of HIV-SN was 42% among patients at an outpatient clinic in Australia; 92% of patients with sensory neuropathy were on ARVs.
- In a cohort of treatment-naive patients, 22.6% had PN without pain whereas 4.6% had symptomatic painful neuropathy; in the majority, PN persisted despite effective control of HIV with ART.
- The risk of PN is higher for patients with advanced HIV infection.
- The annual incidence of DSP among patients with CD4 counts of <200 cells/µL is 7%. In two studies from the 1980s, 30% of patients hospitalized with advanced AIDS had DSP in the absence of ART.
- The prevalence is lower among patients with less-advanced HIV disease.
Prevention and early intervention are vitally important in avoiding or reversing symptoms of neuropathy.
- Initiate ART according to usual guidelines to avoid increased risk of HIV-SN resulting from advanced HIV disease.
- Avoid ARVs (particularly d4T and ddI) associated with neurotoxicity.
- If possible, avoid non-ARV medications that may cause PN.
- Avoid treatment regimens that have additive neurotoxicity (eg, metronidazole for a patient who is receiving isoniazid).
- With patients who develop ARV toxic neuropathy, discontinue the causative ARV if a reasonable substitution can be made.
DSP and ARV toxic neuropathy are clinically indistinguishable, although the timing of symptom onset may help to differentiate the etiology.
Ask about distal numbness and check ankle reflexes.
- Use the ACTG Brief Peripheral Neuropathy Screen (BPNS). This is a validated screening tool for scaling the degree of PN. It includes subjective and objective information, and takes <10 minutes to administer.
- HIV-SN can be diagnosed when a patient exhibits ≥1 symptom specified in the BPNS and 1 of the following: diminished ankle reflexes, reduced vibration sense at the first toe.
- Serial assessment of BPNS scores allows tracking of symptom severity and response to treatment.
|Findings that suggest a different diagnosis|
|Laboratory evaluation||Screen for:
- Goals: relieve pain, halt progression of symptoms.
- Patients taking neurotoxic medications: discontinue these if possible.
- Patients not on ART: consider initiation.
- Pharmacologic treatment often is multimodal, involving several types of medications.
- Consider starting with an anticonvulsant such as gabapentin or pregabalin and titrating to effect.
- Add or use antidepressants: selective serotonin-norepinephrine reuptake inhibitors (SNRIs) (duloxetine or venlafaxine) may improve neuropathy pain, especially for patients with comorbid depression; tricyclic antidepressants (TCAs).
- Add or use topical agents (capsaicin or lidocaine cream or patch) for patients who need additional pain control or cannot tolerate systemic pain medications.
- Do a trial of NSAIDs or acetaminophen; these are useful for some PN patients.
- For severe or recalcitrant symptoms, consider adding a long-acting opioid.
When to Refer
Refer to a pain specialist or neurologist if symptoms are not controlled with initial trials of medication.
|Discontinuation of offending drug (eg, switching from dNRTIs, avoiding combinations with additive neurotoxicity)|
|Initiation of ART|
(for dosages and additional information, see Pain Medications)
|Antidepressants: TCAs and SNRIs|
Potential ARV Interactions
Source: NIAID Adult AIDS Clinical Trials Group
1. Elicit Subjective Symptoms
Ask the subject to rate the severity of each symptom listed in Question 1 on a scale of 01 (mild) to 10 (most severe) for right and left feet and legs. Enter the score for each symptom in the columns marked R (right lower limb) and L (left lower limb). If a symptom has been present in the past, but not since the last visit, enter "00 - Currently Absent." If the symptom has never been present, enter "11 - Always Been Normal."
|a. Pain, aching, or burning in feet, legs|
|b."Pins and needles" in feet, legs|
|c. Numbness (lack of feeling) in feet, legs|
2. Grade Subjective Symptoms
Use the single highest severity score from Question 1 above to obtain a subjective sensory neuropathy score. If all severity scores are "00" or "11," the subjective sensory neuropathy score will equal "0."
Subjective Sensory Neuropathy Score (based on highest severity rating)01 - 03 = grade of 1
04 - 06 = grade of 2
07 - 10 = grade of 3
11 or 00 = grade of 0
3. Evaluate Perception of Vibration
Compress the ends of a 128-Hz tuning fork just hard enough that the sides touch. Place the vibrating tuning fork on a bony prominence on the subject's wrist or hand to be sure that he/she can recognize the vibration or "buzzing" quality of the tuning fork. Again, compress the ends of the tuning fork just hard enough that the sides touch. Immediately place the vibrating tuning fork gently but firmly on the top of the distal interphalangeal (DIP) joint of one great toe and begin counting the seconds. Instruct the subject to tell you when the "buzzing" stops. Repeat for the other great toe.
a. Great toe DIP joint perception of vibration in seconds
b. Vibration perception score
1 = felt 6-10 seconds (mild loss)
2 = felt <5 seconds (moderate loss)
3 = not felt (severe loss)
8 = unable to or did not assess
4. Evaluate Deep Tendon Reflexes
With the subject seated, the examiner uses one hand to press upward on the ball of the foot, dorsiflexing the subject's ankle to 90 degrees. Using a reflex hammer, the examiner then strikes the Achilles tendon. The tendon reflex is felt by the examiner's hand as a plantar flexion of the foot, appearing after a slight delay from the time the Achilles tendon is struck. Use reinforcement by having the subject clench his/her fist before classifying the reflex as absent.
Ankle Reflexes Score0 = absent
1 = hypoactive
2 = normal deep tendon reflexes
3 = hyperactive
4 = clonus
8 = unable to or did not assess
- Cherry CL, Wesselingh SL, Lal L, et al. Evaluation of a clinical screening tool for HIV- associated sensory neuropathies. Neurology. 2005 Dec 13;65(11):1778-81.
- Evans SR, Ellis RJ, Chen H, et al. Peripheral neuropathy in HIV: prevalence and risk factors. AIDS. 2011 Apr 24;25(7):919-28.
- Gonzalez-Duarte A, Robinson-Papp J, Simpson DM. Diagnosis and management of HIV-associated neuropathy. Neurol Clin. 2008 Aug;26(3):821-32.
- McArthur JC, Brew BJ, Nath A. Neurological complications of HIV infection. Lancet Neurol. 2005 Sep;4(9):543-55.
- Phillips TJ, Cherry CL, Cox S, et al. Pharmacological treatment of painful HIV-associated sensory neuropathy: a systematic review and meta-analysis of randomised controlled trials. PLoS One. 2010 Dec 28;5(12):e14433.
- Smyth K, Affandi JS, McArthur JC, et al. Prevalence of and risk factors for HIV-associated neuropathy in Melbourne, Australia 1993-2006. HIV Med. 2007 Sep;8(6):367-73.