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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Management of Medication Toxicity or Intolerance

Nephrotoxic Effects

(Last updated:February 12, 2014; last reviewed:February 12, 2014)

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Table 11i. Antiretroviral Therapy-Associated Adverse Effects and Management Recommendations—Nephrotoxic Effects
Adverse Effects Associated ARVs Onset/Clinical Manifestations Estimated Frequency Risk Factors Prevention/ Monitoring Management
Urolithiasis/ nephrolithiasis IDV, ATV Onset
  • Weeks to months after starting therapy
Clinical findings:
  • Crystalluria, hematuria, pyuria, flank pain, sometimes increased creatinine
IDV-related nephrolithiasis is more common in adults (4%–43%) than in children (0%–20%).

ATV nephrolithiasis is rare.
In adults, high serum IDV concentrations and elevated urine pH (>5.7) associated with persistent pyuria.

Unknown in children.

Prevention:
  • Maintain adequate hydration.
Monitoring:
  • Obtain urinalysis at least every 6–12 months.
Provide adequate hydration and pain control; consider using alternative ARV.
Renal
dysfunction
TDF Onset
  • Variable; in adults, weeks to months after initiation of therapy.
  • Hypophosphatemia appears at a median of 18 months.
Presentation
More Common
  • Increased serum creatinine, proteinuria. Hypophosphatemia, usually asymptomatic, may present with bone and muscle pain, weakness.
Less Common
  • Renal failure, acute tubular necrosis, Fanconi syndrome, proximal renal tubulopathy, interstitial nephritis, nephrogenic diabetes insipidus with polyuria
Adults:
  • ~2% with increased serum creatinine
  • ~0.5% with severe renal complications
Children
  • ~4% with hypophos-phatemia or proximal tubulopathy; higher in advanced HIV infection or concomitant use of ddI
Risk May Be Increased in Children:
  • aged >6 years
  • of Black race, Hispanic/
    Latino ethnicity
  • with advanced HIV infection
  • with concurrent use of ddI or PIs (especially LPV/r), and 
    pre-existing renal dysfunction
  • Risk increases with longer duration of TDF treatment.
Monitor urine protein and glucose or urinalysis, and serum creatinine at intervals of every 3–6 months. For patients taking TDF, some panelists add serum phosphate to the list of routine labs to monitor.

In the presence of persistent proteinuria or glucosuria, or for symptoms of bone pain or muscle pain or weakness, also monitor serum phosphate

Because toxicity risk increases with duration of TDF treatment, frequency of monitoring should not decrease with time. While unproven, routine monitoring intervals of every 3–6 months might be considered. Abnormal values should be confirmed by repeat testing, and frequency of monitoring can be increased if abnormalities are found and TDF is continued.
If TDF is the likely cause, consider using alternative ARV. 
IDV Renal cortical atrophy, acute renal failure Rare Unknown Unknown If IDV is likely cause, consider using alternative ARV. 

Note: IDV not FDA-approved for use in children.
Key to Acronyms: ARV = antiretroviral;, ATV = atazanavir; ddI = didanosine; IDV = indinavir; LPV/r = ritonavir-boosted lopinavir; PI = protease inhibitor; TDF = tenofovir disoproxil fumarate

References

  1. Andiman WA, Chernoff MC, Mitchell C, et al. Incidence of persistent renal dysfunction in human immunodeficiency virus-infected children: associations with the use of antiretrovirals, and other nephrotoxic medications and risk factors. Pediatr Infect Dis J. Jul 2009;28(7):619-625. Available at http://www.ncbi.nlm.nih.gov/pubmed/19561425.
  2. Brennan A, Evans D, Fox M, al e. Renal Insufficiency, Nephrotoxicity, and Mortality among HIV-infected Adults on TDF in a South African Cohort: A Marginal Structural Models Analysis. Paper presented at:18th Conference on Retroviruses and Opportunistic Infections (CROI); February 27-March 3, 2011, 2011; Boston, MA.
  3. Judd A, Boyd KL, Stohr W, et al. Effect of tenofovir disoproxil fumarate on risk of renal abnormality in HIV-1-infected children on antiretroviral therapy: a nested case-control study. AIDS. Feb 20 2010;24(4):525-534. Available at http://www.ncbi.nlm.nih.gov/pubmed/20139752.
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  9. van Rossum AM, Dieleman JP, Fraaij PL, et al. Persistent sterile leukocyturia is associated with impaired renal function in human immunodeficiency virus type 1-infected children treated with indinavir. Pediatrics. Aug 2002;110(2 Pt 1):e19. Available at http://www.ncbi.nlm.nih.gov/pubmed/12165618.
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  12. Cooper RD, Wiebe N, Smith N, Keiser P, Naicker S, Tonelli M. Systematic review and meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients. Clin Infect Dis. Sep 1 2010;51(5):496-505. Available at http://www.ncbi.nlm.nih.gov/pubmed/20673002.
  13. Vigano A, Bedogni G, Manfredini V, et al. Long-term renal safety of tenofovir disoproxil fumarate in vertically HIV-infected children, adolescents and young adults: a 60-month follow-up study. Clin Drug Investig. 2011;31(6):407-415. Available at http://www.ncbi.nlm.nih.gov/pubmed/21528939.
  14. Fraaij PL, Verweel G, van Rossum AM, Hartwig NG, Burger DM, de Groot R. Indinavir/low-dose ritonavir containing HAART in HIV-1 infected children has potent antiretroviral activity, but is associated with side effects and frequent discontinuation of treatment. Infection. Jun 2007;35(3):186-189. Available at http://www.ncbi.nlm.nih.gov/pubmed/17565462.
  15. World Health Organization. Technical update on treatment optimization: Use of efavirenz during pregnancy: A public health perspective. Accessed June 25, 2012. 2012. Available at http://www.who.int/hiv/pub/treatment2/efavirenz/en/.
  16. Purswani M, Patel K, Kopp JB, et al. Tenofovir treatment duration predicts proteinuria in a multiethnic United States Cohort of children and adolescents with perinatal HIV-1 infection. Pediatr Infect Dis J. May 2013;32(5):495-500. Available at http://www.ncbi.nlm.nih.gov/pubmed/23249917.

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