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 Guide Editors
 Editor In Chief
    Joel E. Gallant, MD, MPH

Pharmacology Editor
    Paul Pham, PharmD, BCPS

Zambia Guideline Team
   Peter Mwaba MMed PhD FRCP
   Alywn Mwinga MMed
   Isaac Zulu MMed MPH
   Velepie Mtonga MMed
   Albert Mwango MBChB
   Jabbin Mulwanda MMed FCS
 

 

 

Diagnosis>Organ System>
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Neuropathy, peripheral

Daniel Harrison, M.D., Jeffrey Rumbaugh, M.D., and Anita Venkataramana, M.B.,B.S.
06-25-2009

Zambia Specific Information

  • Peripheral neuropathy is significant concern in Zambia due to frequent use of d4T-based ARV regimens.
  • Pts with preexisting Sx of peripheral neuropathy and those also being treated with isoniazid (INH) should not be started on d4T-containing ARV regimens, since this may worsen Sx.
  • In Zambia, suggested substitutes if a pt develops neuropathy on d4T are AZT or tenofovir.
  • MRI, electrophysiology studies, TENS, gabapentin, lamotrigine, topiramate, capsaicin, tramadol, fentanyl, pregabalin, acetyIcarnitine, and duloxetine not readily available in Zambia.

REFERENCES

Zambia Information Author: Larry William Chang, MD, MPH

PATHOGENS

  • HIV can cause distal sensory neuropathy (HIV-DSP).
  • HIV productively infects perivascular macrophages in both central and peripheral nervous system (PNS): degree of macrophage activation correlates w/ Sx.
  • HIV DNA demonstrated in perineuronal macrophages in dorsal root ganglia of pts with HIV-associated sensory neuropathy.
  • Direct mechanism of neuronal injury may be related to the HIV protein, gp120, which can act as modifier of response to inflammatory cytokines.
  • HIV, HCV: cause vasculitic neuropathy, but rare.  
  • VZV: Post-herpetic neuralgia experienced by some pts.
  • Immune-mediated neuropathies (less common): Guillane-Barre Syndrome (GBS) and chronic inflammatory demyelinating neuropathy (CIDP).
  • Antiretroviral distal sensory neuropathy (ARV-DSP): Can be caused by NRTIs (d4T and ddI). Some studies have also shown neurotoxicity with some PIs (IDV, SQV, and RTV). Exact mechanism of injury unknown, but thought to be due to mitochondrial toxicity from dysfunction of mitochondrial oxidative metabolism.
  • Higher rates of entrapment neuropathies: ulnar neuropathy at elbows, median neuropathy of hands (carpal tunnel syndrome), peroneal neuropathy in legs.
  • Non-HIV-related causes: impaired glucose tolerance, diabetes, vitamin deficiency (B12), alcoholism, thyroid dysfunction, syphilis, other medications (e.g. INH).

CLINICAL

  • Risk factors for neuropathy include low CD4 and high VL. Risk factors for progression include low total neuropathy score (TNS), distal epidermal denervation, and white race.
  • Pts may not recognize Sx; routine questioning during visits may be necessary
  • HIV-DSP and ARV-DSP can coexist. Difficult to clinically differentiate between the two.
  • Pain symmetrical and initially begins in soles of feet. Pts commonly complain of burning, cramping, numbness and/or paresthesias.
  • Consider DDX: neuropathy due to diabetes (which may complicate PI therapy) , alcoholism, B12 deficiency, syphilis, thyroid dysfunction, HCV, malnutrition, advanced age, and IDU.
  • Pts may be asymptomatic: "silent" peripheral neuropathy found on examination only
  • Progressive neuropathy with motor weakness and absent reflexes: think GBS, which usually occurs at the time of primary infection or HIV seroconversion, or CIPD if more chronic.
  • If Sx predominately unilateral, consider entrapment neuropathies.

DIAGNOSIS

  • Hx helps differentiate HIV-DSP from ARV-DSP. Obtain information on NRTI and PI use as well as other agents such as hydroxyurea, INH, and vincristine.
  • PE reveals diminished or absent ankle reflexes compared to knees and "stocking" type sensory loss (decreased pain, temp, and vibratory sensation). Distal weakness can be late feature.
  • Subjective peripheral neuropathy screen (SPNS) has been widely used to screen for neuropathy. Consists of 3 items assessing for presence of paresthesias, pain, and numbness. Easily and quickly administered at bedside.
  • Screen for alcoholism, diabetes (fasting glucose), HCV, B12 deficiency, syphilis and thyroid dysfunction.
  • Electrophysiology studies not necessary except to demonstrate entrapment, polyradiculopathy, and immune-mediated neuropathies.
  • Skin Bx shows decrease in epidermal nerve fiber densities, which correlates with clinical and electrophysiologic evidence of neuropathy. Electrophysiology studies evaluate large nerve fibers and may be normal, even when skin Bx shows substantial damage to small nerve fibers.
  • MRI lumbosacral spine in pts who present with lower extremity polyradiculopathy.
  • Lesions of cervical or thoracic spine can present with Sx suggestive of peripheral neuropathy, usually of lower extremities, but myelopathic examination findings usually present.

TREATMENT

General Principals

  • Stop offending NRTIs whenever possible. Consider stopping potentially offending PIs if Hx strongly suggestive. Usually reverses early Sx within 3 mos.
  • Control blood sugars if diabetic.
  • Stop neurotoxic medications if applicable.
  • Avoid alcohol.
  • Appropriate nutritional status is key to prevent worsening of neuropathy.
  • Fully suppressive ART regimen.
  • Ascertain whether pharmacological intervention necessary.
  • Sx may not be completely reversed with any treatment modality in some pts.
  • Prior pain modifying therapy: dose at termination and duration.
  • Non-pharmacological measures may be needed to supplement medications, eg. transcutaneous electrical nerve stimulation (TENS) unit.
Medications

  • Gabapentin (Neurontin and generic): begin at low doses, increasing gradually as tolerated until pain controlled. Starting dose is 300 mg 3 times daily. Titrate up slowly until an appropriate threshold dose is reached. Side effects: sedation, fatigue, weight gain.
  • Lamotrigine (Lamictal): start at 25 mg twice-daily and slowly escalate to 100 mg twice-daily over 1 mo period to prevent rash, including Stevens-Johnsons syndrome. Randomized controlled trial demonstrated efficacy in ARV-DSP.
  • Topiramate (Topamax and generic): start at 25 mg once-daily and increase by 25 mg q wk to max of 100 mg twice-daily. Adverse effects: kidney stones, memory disturbance, and weight loss.
  • Capsaicin : Single application of high dose (640 mcg/cm2) patch resulted in 12 wks of pain relief in recent controlled trial in painful HIV-DSP. FDA approval for this formulation pending. 
  • Amitriptyline and nortriptyline qhs also effective, but not evaluated in clinical studies.
  • Acute treatment with tramadol 50 mg twice-daily and narcotics reserved for those with excruciating pain.
  • Fentanyl patch (Duragesic): may start at 25 mcg/hr every 3 days and increase dose if required. Caution: PIs can increase fentanyl levels.
  • Pregabalin (Lyrica) approved for painful diabetic neuropathy. Target dose found to be 600 mg/d in divided doses. Recently reported randomized controlled trial revealed no superiority to placebo in HIV-DSP.
  • Acetyl-l-carnitine: Found to be beneficial in clinical trials for ARV-DSP.
  • Duloxetine (Cymbalta): Safety not established in HIV-DSP, no clinical trials underway. Starting dose is 30 mg once-daily, increase up to 60 mg daily. Dose may be increased further if needed.

Drug Comments

DrugRecommendations/Comments
amitriptyline Not commonly used because of anticholinergic side effects, but effective. Start at 10 mg qhs and escalate dose as tolerated. Off-label use for neuropathic pain.
gabapentin Sx relief can take several wks. Generally well tolerated.
lamotrigine For pts who cannot tolerate gabapentin or have inadequate pain relief. Off-label use for painful sensory neuropathy. Has the best evidence for ARV-DSP.
narcotic analgesics Fentanly patches and oxycodone may be tried for refractory pain. Beware of interaction between fentanyl and PIs.
nortriptyline Another tricyclic antidepressant not commonly used. Start at 10-25 mg qhs and escalate dose as tolerated. Off-label use for neuropathic pain.
topiramate Has been helpful but not studied for HIV-related peripheral neuropathy.
pregabalin Not superior to placebo in clinical trials.
duloxetine Use caution in pts on ART, due to lack of safety/interaction data
capsaicin If approved by FDA, possibly in late 2009, high-dose patch may be effective choice.
transcutaneous electric nerve stimulation (TENSMay be helpful in some pts.

REFERENCES

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