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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:2/12/2014; last reviewed:2/12/2014)

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Table 11k. 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 Onset
  • Variable, weeks to months following NRTI initiation
Presentation:
  • Decreased sensation
  • Aching, burning, painful numbness
  • Hyperalgesia (lowered pain threshold)
  • Allodynia (non noxious stimuli cause pain)
  • Decreased or absent ankle reflexes
Distribution: 
  • 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).
HIV-Infected Adults on d4T:
  • Prevalence up to 57% 
  • Incidence rates 6.4–12.1 per 100 person-years
HIV-Infected Adults:
  • Pre-existing neuropathy (e.g., diabetes, alcohol abuse, vitamin B12 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, if possible.

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. 

Data are Insufficient to Allow the Panel to Recommend Use of any of the Following Modalities in Children
  • tricyclic antidepressants
  • gabapentin
  • pregabalin
  • mexilitine
  • lamotrigine
Consider referral to neurologist.
a Peripheral neuropathy may be under-reported 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

References

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  2. Buck WC, Kabue MM, Kazembe PN, Kline MW. Discontinuation of standard first-line antiretroviral therapy in a cohort of 1434 Malawian children. J Int AIDS Soc. 2010;13:31. Available at http://www.ncbi.nlm.nih.gov/pubmed/20691049.
  3. Keswani SC, Pardo CA, Cherry CL, Hoke A, McArthur JC. HIV-associated sensory neuropathies. AIDS. Nov 8 2002;16(16):2105-2117. Available at http://www.ncbi.nlm.nih.gov/pubmed/12409731.
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  6. Canter JA, Robbins GK, Selph D, et al. African mitochondrial DNA subhaplogroups and peripheral neuropathy during antiretroviral therapy. J Infect Dis. Jun 1 2010;201(11):1703-1707. Available at http://www.ncbi.nlm.nih.gov/pubmed/20402593.
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  8. Phillips TJ, Cherry CL, Cox S, Marshall SJ, Rice AS. Pharmacological treatment of painful HIV-associated sensory neuropathy: a systematic review and meta-analysis of randomised controlled trials. PLoS One. 2010;5(12):e14433. Available at http://www.ncbi.nlm.nih.gov/pubmed/21203440.
  9. Menezes CN, Maskew M, Sanne I, Crowther NJ, Raal FJ. A longitudinal study of stavudine-associated toxicities in a large cohort of South African HIV infected subjects. BMC Infect Dis. 2011;11:244. Available at http://www.ncbi.nlm.nih.gov/pubmed/21923929.
  10. Wadley AL, Cherry CL, Price P, Kamerman PR. HIV neuropathy risk factors and symptom characterization in stavudine-exposed South Africans. J Pain Symptom Manage. Apr 2011;41(4):700-706. Available at http://www.ncbi.nlm.nih.gov/pubmed/21145196.
  11. Tukei VJ, Asiimwe A, Maganda A, et al. Safety and tolerability of antiretroviral therapy among HIV-infected children and adolescents in Uganda. J Acquir Immune Defic Syndr. Mar 1 2012;59(3):274-280. Available at http://www.ncbi.nlm.nih.gov/pubmed/22126740.
  12. Webster LR, Peppin JF, Murphy FT, Tobias JK, Vanhove GF. Tolerability of NGX-4010, a capsaicin 8% patch, in conjunction with three topical anesthetic formulations for the treatment of neuropathic pain. J Pain Res. 2012;5:7-13. Available at http://www.ncbi.nlm.nih.gov/pubmed/22328830.
  13. Phan V, Thai S, Choun K, Lynen L, van Griensven J. Incidence of treatment-limiting toxicity with stavudine-based antiretroviral therapy in Cambodia: a retrospective cohort study. PLoS One. 2012;7(1):e30647. Available at http://www.ncbi.nlm.nih.gov/pubmed/22303447.
  14. Palmer M, Chersich M, Moultrie H, Kuhn L, Fairlie L, Meyers T. Frequency of stavudine substitution due to toxicity in children receiving antiretroviral treatment in sub-Saharan Africa. AIDS. Mar 13 2013;27(5):781-785. Available at http://www.ncbi.nlm.nih.gov/pubmed/23169331.