Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

The information in the brief version is excerpted directly from the full-text guidelines. The brief version is a compilation of the tables and boxed recommendations.

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Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs)

Zidovudine

Last Updated: May 22, 2018; Last Reviewed: May 22, 2018

Zidovudine (ZDV, AZT, Retrovir)
Zidovudine (ZDV, AZT, Retrovir)
For additional information see Drugs@FDA: https://www.accessdata.fda.gov/scripts/cder/daf/
Formulations
Capsules: 100 mg
Tablets: 300 mg
Syrup: 10 mg/mL
Concentrate for Injection or Intravenous 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 (scored)
  • [Trizivir] Abacavir 300 mg plus lamivudine 150 mg plus zidovudine 300 mg
Dosing Recommendations Selected Adverse Events
Note: See Antiretroviral Management of Newborns with Perinatal HIV Exposure or Perinatal HIV and Table 12 for information about using zidovudine to prevent perinatal transmission.

Recommended Neonatal Dose for Treatment of HIV by Gestational Age (Weeks) at Birtha
Gestational Age at Birth Oral Zidovudine Dose
≥35 Weeks Birth to Age 4 Weeks:
  • 4 mg/kg orally twice daily or alternative simplified weight band dosing

Simplified Weight Band Dosing for Infants with a Gestational Age ≥35 Weeks at Birth:
Note: The doses in this table provide approximately 4 mg/kg orally twice daily from birth to age 4 weeks.
Weight Band Volume Zidovudine 10 mg/mL Oral Syrup Twice Daily
2 kg to <3 kg 1 mL
3 kg to <4 kg 1.5 mL
4 kg to <5 kg 2 mL

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 premature infants who are diagnosed with HIV, the time to change the dose to continuation dose varies with postgestational age and clinical status of the neonate (see the Special Issues for Neonates section below).

Note: For infants who are unable to tolerate oral agents, the intravenous (IV) dose should be 75% of the oral dose, but the dosing interval should remain the same.


Infant (Aged ≥35 Weeks Post-Conception and ≥4 Weeks Post-Delivery, Weighing ≥4 kg) and Child Dose

Zidovudine 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

Alternative 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 (Weighing ≥30 kg) and Adult Dose:
  • 1 tablet twice daily
[Trizivir] Abacavir plus Lamivudine plus Zidovudine
Adolescent (Weighing ≥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
  • Lipodystrophy and lipoatrophy
  • Myopathy (associated with prolonged use of zidovudine) and myositis
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 (IV) dose should be 75% of the oral dose, but the dosing interval should remain the same.
  • When using fixed-dose combination (FDC) tablets that contain zidovudine, see other sections of the Drug Appendix for special instructions and additional information about the individual components of the FDC.
Metabolism/Elimination
  • Metabolized primarily in the liver to zidovudine glucuronide, which is renally excreted.
  • Zidovudine is phosphorylated intracellularly to active zidovudine-triphosphate.
Zidovudine Dosing in Patients with Renal Impairment:
  • Dose adjustment is required in renal insufficiency.
Zidovudine Dosing in Patients with Hepatic Impairment:
  • Dose may need to be reduced in patients with hepatic impairment.
  • Do not use FDC products (e.g., Combivir, Trizivir) in patients with creatinine clearance <50 mL/min or in patients who are on dialysis or who have impaired hepatic function.

Drug Interactions (see also the Adult and Adolescent Guidelines and HIV Drug Interaction Checker)

  • 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 that affect 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. Neutropenia may occur more frequently in infants receiving both lamivudine and zidovudine than in infants receiving only zidovudine.1
  • Less common (more severe): Myopathy (associated with prolonged use), myositis, and liver toxicity. Cases of 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 and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use

Approval
Zidovudine is frequently included as a component of the NRTI backbone for antiretroviral therapy (ART) and has been studied in children in combination with other NRTIs, including abacavir and lamivudine.7-23 Pediatric experience with zidovudine both for treating HIV and for preventing perinatal transmission is extensive. However, the mitochondrial toxicity of zidovudine leads many experts to favor the use of abacavir or tenofovir alafenamide in cases where patient age and the results of viral resistance testing do not restrict the use of these drugs.

Efficacy in Clinical Trials
Zidovudine in Combination with Other NRTIs

  • Zidovudine with lamivudine has been extensively studied in children and has been a part of ART regimens in many trials.
  • Safety and efficacy of zidovudine combined with lamivudine was compared to abacavir/lamivudine and stavudine/lamivudine in children aged <5 years in the CHAPAS-3 study. All regimens also contained either nevirapine or efavirenz. All NRTIs had low toxicity and good clinical, immunologic, and virologic responses.24
  • Zidovudine/abacavir and zidovudine/lamivudine had lower rates of viral suppression and more toxicity leading to drug modification than did abacavir/lamivudine in a European pediatric study.25,26

Special Issues in Neonates
Perinatal trial PACTG 076 established that zidovudine prophylaxis given to the mother during pregnancy, labor, and delivery, and given to the newborn reduced the risk of perinatal transmission of HIV by nearly 70%27 (see Antiretroviral Management of Newborns with Perinatal HIV Exposure or Perinatal HIV for further discussion on the use of zidovudine for the prevention of perinatal transmission of HIV). Zidovudine 4 mg/kg body weight every 12 hours is recommended for neonates and infants with ≥35 weeks’ gestation for prevention of perinatal HIV transmission. Infants who are HIV-exposed but uninfected should continue on the prophylactic dose for 4 to 6 weeks, depending on the assessment of risk for perinatal transmission and gestational age at time of delivery.

For full-term neonates who receive an HIV diagnosis, the zidovudine dose should be increased at age 4 weeks to the continuation dose (see dosing table). 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 increase the dose from the initial dose varies with postgestational age and the clinical status of the neonate. On the basis of modeling and the pharmacokinetics (PK) of zidovudine in premature infants, the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV (the Panel) recommends switching to a dose of zidovudine 12 mg/kg twice daily at postgestational age 6 to 8 weeks in infants born at ≥30 to <35 weeks. For infants who are born at <30 weeks, change to zidovudine 12 mg/kg twice daily at a postgestational age of 8 to 10 weeks.28 Careful clinical assessment of the infant, evaluation of hepatic and renal function, and review of concomitant medications should be performed prior to increasing the zidovudine dose to that recommended for full-term infants.

Pharmacokinetics

Overall, zidovudine PK in pediatric patients aged >3 months are similar to those seen 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 the low intracellular zidovudine triphosphate concentrations seen with 600-mg, once-daily dosing in adolescents.29 PK studies such as PACTG 331 demonstrate that dose adjustments are necessary for premature infants because they have reduced clearance of zidovudine compared with the clearance observed in term newborns of similar postnatal age.8 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.19

Zidovudine

Source: Mirochnick, M. Antiretroviral pharmacology in pregnant women and their newborns. Presented at: Advances in Pediatric AIDS. 1999. Montreal, CA.

The rate-limiting step in phosphorylation of zidovudine to active zidovudine triphosphate is the limited amount of thymidylate kinase. Increasing doses of zidovudine will lead to increased zidovudine plasma concentrations and increased intracellular concentrations of zidovudine monophosphate but not zidovudine diphosphate or zidovudine triphosphate. In 31 infants receiving zidovudine for prevention of perinatal transmission, intracellular zidovudine metabolites were measured after delivery. Plasma zidovudine and intracellular zidovudine monophosphate decreased by roughly 50% between postdelivery Day 1 and Day 28, whereas zidovudine diphosphate and zidovudine triphosphate remained low throughout the sampling period.30 On the basis of poor correlation between zidovudine dose and intracellular zidovudine triphosphate concentrations, a simplified dosing approach can be used for infants ≥35 weeks gestation receiving approximately zidovudine 4 mg/kg twice daily oral dosing for the first 4 weeks of life (see the dosing table in summary table above). These volumes provide approximately zidovudine 4 mg/kg per dose using the 10 mg/mL oral syrup. This approach should simplify the minor dose adjustments that are commonly made based on changes in infant weight during zidovudine use in the first 4 weeks of life. These changes in weight and small differences in zidovudine dose will have minor effects on the intracellular concentrations of zidovudine triphosphate. This approach should make it easier for caregivers to administer zidovudine oral syrup to their infants.

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.7,8,31

Incidence of hematological toxicity was investigated in the ARROW study, which randomized Ugandan/Zimbabwean treatment-naive children to receive either zidovudine-containing regimens or abacavir-containing regimens. The incidence of severe anemia was similar regardless of zidovudine use, and this finding suggests that advanced HIV disease contributed to low hemoglobin values. Zidovudine use was associated with severe neutropenia in a small number of children.32

Zidovudine is associated with greater mitochondrial toxicity when compared to abacavir and tenofovir disoproxil fumarate but less than stavudine.33,34

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 U.S.-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 Pregnant Women with HIV Infection and Prevention of Perinatal Transmission. Recommendations for the use of antiretroviral drugs in pregnant women with HIV infection and interventions to reduce perinatal HIV transmission in the United States. 2018. Available at http://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf.
  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;61(2):270-280. Available at http://www.ncbi.nlm.nih.gov/pubmed/25838291.
  7. 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.
  8. 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.
  9. 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.
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  12. 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.
  13. 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.
  14. 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.
  15. McKinney RE, Jr., Johnson GM, Stanley K, et al. A randomized study of combined zidovudine-lamivudine versus didanosine monotherapy in children with symptomatic therapy-naive HIV-1 infection. The Pediatric AIDS Clinical Trials Group Protocol 300 Study Team. J Pediatr. 1998;133(4):500-508. Available at http://www.ncbi.nlm.nih.gov/pubmed/9787687.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. Mulenga V, Musiime V, Kekitiinwa A, et al. Abacavir, zidovudine, or stavudine as paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial. Lancet Infect Dis. 2016;16(2):169-179. Available at http://www.ncbi.nlm.nih.gov/pubmed/26481928.
  25. Green H, Gibb DM, Walker AS, et al. Lamivudine/abacavir maintains virological superiority over zidovudine/lamivudine and zidovudine/abacavir beyond 5 years in children. AIDS. 2007;21(8):947-955. Available at http://www.ncbi.nlm.nih.gov/pubmed/17457088.
  26. Paediatric European Network for Treatment of AIDS (PENTA). Comparison of dual nucleoside-analogue reverse-transcriptase inhibitor regimens with and without nelfinavir in children with HIV-1 who have not previously been treated: the PENTA 5 randomised trial. Lancet. 2002;359(9308):733-740. Available at http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=11888583&query_hl=42.
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  28. 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.
  29. 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.
  30. Kinai E, Kato S, Hosokawa S, et al. High plasma concentrations of zidovudine (AZT) do not parallel intracellular concentrations of AZT-triphosphates in infants during prevention of mother-to-child HIV-1 transmission. J Acquir Immune Defic Syndr. 2016;72(3):246-253. Available at http://www.ncbi.nlm.nih.gov/pubmed/26859826.
  31. 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.
  32. Musiime V, Cook A, Nahirya Ntege P, et al. The effect of long-term zidovudine on hematological parameters in the ARROW randomized trial. Presented at: The 22nd Conference on Retroviruses and Opportunistic Infections. 2015. Seattle, WA.
  33. Moyle GJ, Sabin CA, Cartledge J, et al. A randomized comparative trial of tenofovir DF or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. AIDS. 2006;20(16):2043-2050. Available at http://www.ncbi.nlm.nih.gov/pubmed/17053350.
  34. Carr A, Workman C, Smith DE, et al. Abacavir substitution for nucleoside analogs in patients with HIV lipoatrophy: a randomized trial. JAMA. 2002;288(2):207-215. Available at http://www.ncbi.nlm.nih.gov/pubmed/12095385.

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