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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Management of Medication Toxicity or Intolerance

Peripheral Nervous System Toxicity

(Last updated: March 1, 2016; last reviewed: March 1, 2016)

Table 12k. Antiretroviral Therapy-Associated Adverse Effects and Management Recommendations—Peripheral Nervous System Toxicity
Adverse Effects Associated ARVs Onset/Clinical Manifestations Estimated Frequencya Risk Factors Prevention/ Monitoring Management
ARV Toxic Neuropathyb d4T, ddI


  • Variable; weeks to months following NRTI initiation.
  • Decreased sensation
  • Aching, burning, painful numbness
  • Hyperalgesia (lowered pain threshold)
  • Allodynia (non noxious stimuli cause pain)
  • Decreased or absent ankle reflexes
  • Bilateral soles of feet, ascending to legs and fingertips
HIV-Infected Children:
  • 1.13% prevalence (baseline 2001); incidence 0.23 per 100 person-years (2001–2006) in a U.S. cohort.
  • <1% discontinued d4T because of neuropathy in 3 large African cohorts (aged 1 month–18 years; median follow-up 1.8–3.2 years).
  • 42 out of 174 (24%) in a South African cohort were diagnosed with peripheral neuropathy. 86% were taking d4T, and use of ddI was an additional risk factor.
  • 4/40 (10%) Indian children taking d4T had abnormal nerve conduction tests.
HIV-Infected Adults on d4T:
  • Prevalence up to 57% 
  • Incidence rates of 6.4–12.1 per 100 person-years
HIV-Infected Adults:
  • Preexisting neuropathy (e.g., diabetes, alcohol abuse, vitamin B-12 deficiency)
  • Elevated triglyceride levels
  • Older age
  • Poor nutrition
  • More advanced HIV disease
  • Concomitant use of other neurotoxic agents (e.g., INH)
  • Some mitochondrial DNA haplogroups may have increased risk.

Limit use of d4T and ddI.

As part of routine care, monitor for symptoms and signs of peripheral neuropathy.

Discontinue offending agent.

Persistent pain can be difficult to treat; topical capsaicin 8% may be helpful.

Consider referral to a neurologist. 

Data Are Insufficient to Allow the Panel to Recommend Use of Any of the Following Modalities in Children:

  • Tricyclic antidepressants
  • Gabapentin
  • Pregabalin
  • Mexiletine
  • Lamotrigine
  • Acupuncture or other complementary approaches
a Peripheral neuropathy may be underreported in children because symptoms are difficult to evaluate in young children.
b HIV infection itself may cause a distal sensory neuropathy that is phenotypically identical to ARV toxic neuropathy.

Key to Acronyms: ARV = antiretroviral; d4T = stavudine; ddI = didanosine; INH = isoniazid; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor


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