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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: March 5, 2015; last reviewed: March 5, 2015)

Table 13i. 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
ATV

Although DRV causes crystalluria, it is not associated with increased nephrolithiasis risk.
Onset:
  • Weeks to months after starting therapy
Clinical Findings:
  • Crystalluria, hematuria, pyuria, flank pain, sometimes increased creatinine
ATV-related nephrolithiasis occurs in <10%. In adults, elevated urine pH (>5.7) 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.
  • Hypophos-phatemia appears at a median of 18 months.
  • Glucosuria may have onset after a year of therapy.
Presentation:
More Common:
  • Increased serum creatinine, proteinuria, normoglycemic glucosuria. Hypophos-phatemia, 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 with prolonged TDF therapy, 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
    preexisting renal dysfunction
  • Risk increases with longer duration of TDF treatment.
Monitor urine protein and glucose or urinalysis, and serum creatinine at 3- to 6-month intervals. 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.
Elevation in Serum Creatinine DTG,
COBI, RPV
Onset:
  • Within a month of starting treatment
Presentation:
  • Asymptomatic. These drugs decrease renal tubular secretion of creatinine, leading to an increase in measured serum creatinine without a true change in GFR.
Common

Need to distinguish between true change in GFR and other causes
Monitor serum creatinine. Assess for renal dysfunction if serum creatinine increases by >0.4 mg/dL. No need to change therapy. Reassure patient about the benign nature of the laboratory abnormality.

Key to Acronyms: ARV = antiretroviral; ATV = atazanavir; COBI = cobicistat; ddI = didanosine; DRV = darunavir; DTG = dolutegravir; GFR = glomerular filtration rate; LPV/r = ritonavir-boosted lopinavir; PI = protease inhibitor; RPV = rilpivirine; 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. 2009;28(7):619-625. Available at http://www.ncbi.nlm.nih.gov/pubmed/19561425.
  2. Brennan A, Evans D, Fox M, et al. Renal Insufficiency, Nephrotoxicity, and Mortality among HIV-infected Adults on TDF in a South African Cohort: A Marginal Structural Models Analysis. Presented at: 18th Conference on Retroviruses and Opportunistic Infections. 2011. Boston, MA.
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  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. 2007;35(3):186-189. Available at http://www.ncbi.nlm.nih.gov/pubmed/17565462.
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  18. de Lastours V, Ferrari Rafael De Silva E, Daudon M, et al. High levels of atazanavir and darunavir in urine and crystalluria in asymptomatic patients. J Antimicrob Chemother. 2013;68(8):1850-1856. Available at http://www.ncbi.nlm.nih.gov/pubmed/23599359.
  19. German P, Liu HC, Szwarcberg J, et al. Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function. J Acquir Immune Defic Syndr. 2012;61(1):32-40. Available at http://www.ncbi.nlm.nih.gov/pubmed/22732469.
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