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Table of Contents

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs)

Zidovudine

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

Zidovudine (ZDV, AZT, Retrovir)
Zidovudine (ZDV, AZT, Retrovir)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/
Formulations

Capsules: 100 mg
Tablets: 300 mg
Syrup: 10 mg/mL
Concentrate for Injection or Intravenous (IV) Infusion: 10 mg/mL
Generic Formulations: Zidovudine capsules, tablets, syrup, and injection are approved by the Food and Drug Administration for manufacture and distribution in the United States.
Fixed-Dose Combination Tablets:

  • [Combivir and generic] Lamivudine 150 mg plus zidovudine 300 mg
  • [Trizivir] Abacavir 300 mg plus lamivudine 150 mg plus zidovudine 300 mg
     
Dosing Recommendations Selected Adverse Events
Recommended Neonatal Dosing for Treatment of HIV Infectiona
Gestational Age (weeks) Zidovudine Oral Dosing:
  • Twice-Daily Dosing
Note: For infants unable to tolerate oral agents, the IV dose should be 75% of the oral dose while maintaining the same dosing interval.
≥35 weeks Birth to Age 4 Weeks:
  • 4 mg/kg orally twice daily
Aged >4 Weeks:
  • 12 mg/kg orally twice daily
≥30 to <35 weeks Birth to Age 2 Weeks:
  • 2 mg/kg orally twice daily
Aged 2 Weeks to 6 to 8 Weeks:
  • 3 mg/kg orally twice daily
Aged >6 to 8 Weeks:
  • 12 mg/kg orally twice daily
<30 weeks Birth to Age 4 Weeks:
  • 2 mg/kg orally twice daily
Aged 4 Weeks to 8 to 10 Weeks:
  • 3 mg/kg orally twice daily
Aged >8 to 10 Weeks:
  • 12 mg/kg orally twice daily
a For prevention of perinatal transmission see Perinatal Guidelines


Infant/Child Dose (Age ≥35 Weeks Post-Conception and at Least 4 Weeks Post-Delivery):

Weight-Based Dosing
Body Weight Twice-Daily Dosing
4 kg to <9 kg 12 mg/kg
9 kg to <30 kg 9 mg/kg
≥30 kg 300 mg
Note: Weight-based dosing table should be used for infants aged ≥35 weeks post-conception, at least 4 weeks post-delivery with body weight ≥4 kg.


Body Surface Area Dosing:
  • Oral: 180–240 mg/m2 body surface area every 12 hours

Adolescent (Aged ≥18 Years) and Adult Dose:
  • 300 mg twice daily

[Combivir and generic] Lamivudine plus Zidovudine
Adolescent (Weight ≥30 kg) and Adult Dose:
  • 1 tablet twice daily

[Trizivir] Abacavir plus Lamivudine plus Zidovudine
Adolescent (Weight ≥40 kg) and Adult Dose:
  • 1 tablet twice daily
  • Bone marrow suppression: macrocytosis with or without anemia, neutropenia
  • Nausea, vomiting, headache, insomnia, asthenia
  • Lactic acidosis/severe hepatomegaly with hepatic steatosis
  • Nail pigmentation
  • Hyperlipidemia
  • Insulin resistance/diabetes mellitus
  • Lipoatrophy
  • Myopathy
Special Instructions
  • Give zidovudine without regard to food.
  • If substantial granulocytopenia or anemia develops in patients receiving zidovudine, it may be necessary to discontinue therapy until bone marrow recovery is observed. In this setting, some patients may require erythropoietin or filgrastim injections or transfusions of red blood cells.
  • For infants unable to tolerate oral agents, the intravenous dose for newborns should be reduced by 25% while maintaining the same dosing interval.
Metabolism/Elimination
  • Metabolized primarily in the liver to zidovudine glucuronide, which is renally excreted.
  • Zidovudine is phosphorylated intracellularly to active zidovudine-triphosphate.
  • Dosing in patients with renal impairment:
    Dosage adjustment is required in renal insufficiency.
  • Dosing in patients with hepatic impairment:
    Decreased dosing may be required in patients with hepatic impairment.
  • Do not use fixed-dose combination products (e.g., Combivir, Trizivir) in patients with creatinine clearance <50 mL/min, on dialysis, or who have impaired hepatic function.

Drug Interactions (see also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents and http://www.hiv-druginteractions.org/)

  • Other nucleoside reverse transcriptase inhibitors (NRTIs): Zidovudine should not be administered in combination with stavudine because of in vitro virologic antagonism.
  • Bone marrow suppressive/cytotoxic agents including ganciclovir, valganciclovir, interferon alfa, and ribavirin: These agents may increase the hematologic toxicity of zidovudine.
  • Nucleoside analogues affecting DNA replication: Nucleoside analogues such as ribavirin antagonize in vitro antiviral activity of zidovudine.
  • Doxorubicin: Simultaneous use of doxorubicin and zidovudine should be avoided. Doxorubicin may inhibit the phosphorylation of zidovudine to its active form.

Major Toxicities

  • More common: Hematologic toxicity, including granulocytopenia and anemia, particularly in patients with advanced HIV-1 disease. Headache, malaise, nausea, vomiting, and anorexia. Incidence of neutropenia may be increased in infants receiving lamivudine.1
  • Less common (more severe): Myopathy (associated with prolonged use), myositis, and liver toxicity. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported. Fat maldistribution.
  • Rare: Increased risk of hypospadias after first-trimester exposure to zidovudine observed in one cohort study.2 Possible increased risk of cardiomyopathy.3 Possible association between first-trimester exposure to zidovudine and congenital heart defects (see Teratogenicity in the Perinatal Guidelines).4-6

Resistance

The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations (see http://iasusa.org/sites/default/files/tam/october_november_2015.pdf#page=10) and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation (see http://hivdb.stanford.edu/pages/GRIP/ zidovudine.html).

Resistance mutations were shown to be present in 29% (5 of 17) of infants born to mothers who received zidovudine during pregnancy.7

Pediatric Use

Approval
Zidovudine is frequently included as a component of the NRTI backbone for combination antiretroviral therapy (ART).8-24 Pediatric experience with zidovudine both for treatment of HIV and for prevention of perinatal transmission is extensive.

Special Issues in Neonates
Perinatal trial PACTG 076 established that zidovudine prophylaxis given during pregnancy, labor, and delivery, and to the newborn reduced risk of perinatal transmission of HIV by nearly 70%25 (see the Perinatal Guidelines for further discussion on the use of zidovudine for the prevention of perinatal transmission of HIV). Although the PACTG 076 study used a zidovudine regimen of 2 mg/kg every 6 hours, data from many international studies support twice-daily oral infant dosing for prophylaxis. Zidovudine 4 mg/kg body weight every 12 hours (prophylactic dose) is now recommended for neonates/infants ≥35 weeks of gestation for prevention of transmission (see the Perinatal Guidelines). HIV-exposed but uninfected infants should be continued on the prophylactic dose for 4 to 6 weeks (see Perinatal Guidelines).

For full-term neonates who are diagnosed with HIV infection before age 4 weeks, the zidovudine dose should be increased at age 4 weeks to the continuation dose (see table above). HIV-exposed but uninfected infants should be continued on the initial prophylactic dose until age 6 weeks (see the Perinatal Guidelines). The activity of the enzymes responsible for glucuronidation is low at birth and increases dramatically over the first 4 to 6 weeks of life in full-term neonates.

For premature infants who are diagnosed with HIV infection, the time to change the dose to continuation dose varies with post-gestational age and clinical status of the neonate. Based on modeling and pharmacokinetics (PK) of zidovudine in premature infants, for infants born at ≥30 to <35 weeks change to 12 mg/kg/dose at post-gestational age 6 to 8 weeks and for infants <30 weeks, change to 12 mg/kg at post-gestational age 8 to 10 weeks.26 Careful clinical assessment of the infant, evaluation of hepatic and renal function, and review of concomitant medications should be performed prior to increasing zidovudine dose to that recommended for full-term infants.

Pharmacokinetics

Overall, zidovudine PK in pediatric patients aged >3 months are similar to those in adults. Zidovudine undergoes intracellular metabolism to its active form, zidovudine triphosphate. Although the mean half-life of intracellular zidovudine triphosphate (9.1 hours) is considerably longer than that of unmetabolized zidovudine in plasma (1.5 hours), once-daily zidovudine dosing is not recommended because of low intracellular zidovudine triphosphate concentrations seen with 600-mg, once-daily dosing in adolescents.27 PK studies, such as PACTG 331, demonstrate that dose adjustments are necessary for premature infants because they have reduced clearance of zidovudine compared with term newborns of similar postnatal age.9

Zidovudine has good central nervous system (CNS) penetration (cerebrospinal fluid-to-plasma concentration ratio = 0.68) and has been used in children with HIV-related CNS disease.20

Toxicity

Several studies suggest that the adverse hematologic effects of zidovudine may be concentration-dependent, with a higher risk of anemia and neutropenia in patients with higher mean area under the curve.8,9,28

Incidence of hematological toxicity was compared in the ARROW study of Ugandan/Zimbabwean treatment naive children randomized to zidovudine- versus abacavir-containing regimens. The incidence of severe anemia was similar regardless of zidovudine use and suggests that advanced HIV disease contributed to low hemoglobin values. Zidovudine use was associated with severe neutropenia in a small number of children.29

While the incidence of cardiomyopathy associated with perinatal HIV infection has decreased dramatically since use of ART became routine, a regimen containing zidovudine may increase the risk.3 Recent analysis of data from a US-based, multicenter prospective cohort study (PACTG 219/219C) found that ongoing zidovudine exposure was independently associated with a higher rate of cardiomyopathy.3

References 

  1. Nielsen-Saines K, Watts DH, Veloso VG, et al. Three postpartum antiretroviral regimens to prevent intrapartum HIV infection. N Engl J Med. 2012;366(25):2368-2379. Available at http://www.ncbi.nlm.nih.gov/pubmed/22716975.
  2. Watts DH, Li D, Handelsman E, et al. Assessment of birth defects according to maternal therapy among infants in the Women and Infants Transmission Study. J Acquir Immune Defic Syndr. 2007;44(3):299-305. Available at http://www.ncbi.nlm.nih.gov/pubmed/17159659.
  3. Patel K, Van Dyke RB, Mittleman MA, et al. The impact of HAART on cardiomyopathy among children and adolescents perinatally infected with HIV-1. AIDS. 2012;26(16):2027-2037. Available at http://www.ncbi.nlm.nih.gov/pubmed/22781228.
  4. Sibiude J, Mandelbrot L, Blanche S, et al. Association between prenatal exposure to antiretroviral therapy and birth defects: an analysis of the French perinatal cohort study (ANRS CO1/CO11). PLoS Med. 2014;11(4):e1001635. Available at http://www.ncbi.nlm.nih.gov/pubmed/24781315.
  5. Panel on Treatment of HIV-Infected Pregnant Women and Prevention of Perinatal Transmission. Recommendations for use of antiretroviral drugs in pregnant HIV-1-infected women for maternal health and interventions to reduce perinatal HIV transmission in the United States. 2014. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. Accessed November 2, 2015.
  6. Sibiude J, Le Chenadec J, Bonnet D, et al. In Utero Exposure to Zidovudine and Heart Anomalies in the ANRS French Perinatal Cohort and the Nested PRIMEVA Randomized Trial. Clin Infect Dis. 2015. Available at http://www.ncbi.nlm.nih.gov/pubmed/25838291.
  7. Kovacs A, Cowles MK, Britto P, et al. Pharmacokinetics of didanosine and drug resistance mutations in infants exposed to zidovudine during gestation or postnatally and treated with didanosine or zidovudine in the first three months of life. Pediatr Infect Dis J. 2005;24(6):503-509. Available at http://www.ncbi.nlm.nih.gov/pubmed/15933559.
  8. Balis FM, Pizzo PA, Murphy RF, et al. The pharmacokinetics of zidovudine administered by continuous infusion in children. Ann Intern Med. 1989;110(4):279-285. Available at http://www.ncbi.nlm.nih.gov/pubmed/2643914.
  9. Capparelli EV, Mirochnick M, Dankner WM, et al. Pharmacokinetics and tolerance of zidovudine in preterm infants. J Pediatr. 2003;142(1):47-52. Available at http://www.ncbi.nlm.nih.gov/pubmed/12520254.
  10. Chadwick EG, Rodman JH, Britto P, et al. Ritonavir-based highly active antiretroviral therapy in human immunodeficiency virus type 1-infected infants younger than 24 months of age. Pediatr Infect Dis J. 2005;24(9):793-800. Available at http://www.ncbi.nlm.nih.gov/pubmed/16148846.
  11. Englund JA, Baker CJ, Raskino C, et al. Zidovudine, didanosine, or both as the initial treatment for symptomatic HIV-infected children. AIDS Clinical Trials Group (ACTG) Study 152 Team. N Engl J Med. 1997;336(24):1704-1712. Available at http://www.ncbi.nlm.nih.gov/pubmed/9182213.
  12. Jankelevich S, Mueller BU, Mackall CL, et al. Long-term virologic and immunologic responses in human immunodeficiency virus type 1-infected children treated with indinavir, zidovudine, and lamivudine. J Infect Dis. 2001;183(7):1116-1120. Available at http://www.ncbi.nlm.nih.gov/pubmed/11237839.
  13. King JR, Kimberlin DW, Aldrovandi GM, Acosta EP. Antiretroviral pharmacokinetics in the paediatric population: a review. Clinical pharmacokinetics. 2002;41(14):1115-1133. Available at http://www.ncbi.nlm.nih.gov/pubmed/12405863.
  14. Luzuriaga K, Bryson Y, Krogstad P, et al. Combination treatment with zidovudine, didanosine, and nevirapine in infants with human immunodeficiency virus type 1 infection. N Engl J Med. 1997;336(19):1343-1349. Available at http://www.ncbi.nlm.nih.gov/pubmed/9134874.
  15. McKinney RE, Jr., Maha MA, Connor EM, et al. A multicenter trial of oral zidovudine in children with advanced human immunodeficiency virus disease. The Protocol 043 Study Group. N Engl J Med. 1991;324(15):1018-1025. Available at http://www.ncbi.nlm.nih.gov/pubmed/1672443.
  16. McKinney RE, Jr., Johnson GM, Stanley K, et al, with The Pediatric AIDS Clinical Trials Group Protocol 300 Study Team. A randomized study of combined zidovudine-lamivudine versus didanosine monotherapy in children with symptomatic therapy-naive HIV-1 infection. J Pediatr. 1998;133(4):500-508. Available at http://www.ncbi.nlm.nih.gov/pubmed/9787687.
  17. Mueller BU, Nelson RP, Jr., Sleasman J, et al. A phase I/II study of the protease inhibitor ritonavir in children with human immunodeficiency virus infection. Pediatrics. 1998;101(3 Pt 1):335-343. Available at http://www.ncbi.nlm.nih.gov/pubmed/9480994.
  18. Mueller BU, Sleasman J, Nelson RP, Jr., et al. A phase I/II study of the protease inhibitor indinavir in children with HIV infection. Pediatrics. 1998;102(1 Pt 1):101-109. Available at http://www.ncbi.nlm.nih.gov/pubmed/9651421.
  19. Palacios GC, Palafox VL, Alvarez-Munoz MT, et al. Response to two consecutive protease inhibitor combination therapy regimens in a cohort of HIV-1-infected children. Scand J Infect Dis. 2002;34(1):41-44. Available at http://www.ncbi.nlm.nih.gov/pubmed/11874163.
  20. Pizzo PA, Eddy J, Falloon J, et al. Effect of continuous intravenous infusion of zidovudine (AZT) in children with symptomatic HIV infection. N Engl J Med. 1988;319(14):889-896. Available at http://www.ncbi.nlm.nih.gov/pubmed/3166511.
  21. Saez-Llorens X, Nelson RP, Jr., Emmanuel P, et al. A randomized, double-blind study of triple nucleoside therapy of abacavir, lamivudine, and zidovudine versus lamivudine and zidovudine in previously treated human immunodeficiency virus type 1-infected children. The CNAA3006 Study Team. Pediatrics. 2001;107(1):E4. Available at http://www.ncbi.nlm.nih.gov/pubmed/11134468.
  22. van Rossum AM, Geelen SP, Hartwig NG, et al. Results of 2 years of treatment with protease-inhibitor--containing antiretroviral therapy in dutch children infected with human immunodeficiency virus type 1. Clin Infect Dis. 2002;34(7):1008-1016. Available at http://www.ncbi.nlm.nih.gov/pubmed/11880968.
  23. Bergshoeff AS, Fraaij PL, Verweij C, et al. Plasma levels of zidovudine twice daily compared with three times daily in six HIV-1-infected children. J Antimicrob Chemother. 2004;54(6):1152-1154. Available at http://www.ncbi.nlm.nih.gov/pubmed/15537694.
  24. Nachman SA, Stanley K, Yogev R, et al. Nucleoside analogs plus ritonavir in stable antiretroviral therapy-experienced HIV-infected children: a randomized controlled trial. Pediatric AIDS Clinical Trials Group 338 Study Team. JAMA. 2000;283(4):492-498. Available at http://www.ncbi.nlm.nih.gov/pubmed/10659875.
  25. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994;331(18):1173-1180. Available at http://www.ncbi.nlm.nih.gov/pubmed/7935654.
  26. Capparelli EV, Englund JA, Connor JD, et al. Population pharmacokinetics and pharmacodynamics of zidovudine in HIV-infected infants and children. J Clin Pharmacol. 2003;43(2):133-140. Available at http://www.ncbi.nlm.nih.gov/pubmed/12616665.
  27. Flynn PM, Rodman J, Lindsey JC, et al. Intracellular pharmacokinetics of once versus twice daily zidovudine and lamivudine in adolescents. Antimicrob Agents Chemother. 2007;51(10):3516-3522. Available at http://www.ncbi.nlm.nih.gov/pubmed/17664328.
  28. Fillekes Q, Kendall L, Kitaka S, et al. Pharmacokinetics of zidovudine dosed twice daily according to World Health Organization weight bands in Ugandan HIV-infected children. Pediatr Infect Dis J. 2014;33(5):495-498. Available at http://www.ncbi.nlm.nih.gov/pubmed/24736440.
  29. Musiime V, Cook A, Nahirya Ntege P, et al. The effect of long-term zidovudine on hematological parameters in the ARROW randomized trial. Abstract #919. Presented at: The 22nd Conference on Retroviruses and Opportunistic Infections. 2015. Seattle, WA.

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