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: April 16, 2019; Last Reviewed: April 16, 2019

Zidovudine (ZDV, Retrovir)
Zidovudine (ZDV, 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/zidovudine 300 mg (scored)
  • [Trizivir and Generic] Abacavir 300 mg/lamivudine 150 mg/zidovudine 300 mg
Dosing Recommendations Selected Adverse Events
Note: Zidovudine is frequently used in neonates to prevent perinatal transmission of HIV. 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 at Birtha
Gestational Age at Birth Oral Zidovudine Dose
≥35 weeks Birth to Age 4 Weeks:
  • Zidovudine 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 zidovudine 4 mg/kg orally twice daily from birth to age 4 weeks.
Weight Band Volume of 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:
  • Zidovudine 12 mg/kg orally twice daily
≥30 weeks to <35 weeks Birth to Age 2 Weeks:
  • Zidovudine 2 mg/kg orally twice daily
Aged 2 Weeks to 6 to 8 Weeks:
  • Zidovudine 3 mg/kg orally twice daily
Aged >6 Weeks to 8 Weeks:
  • Zidovudine 12 mg/kg orally twice daily
<30 weeks Birth to Age 4 Weeks:
  • Zidovudine 2 mg/kg orally twice daily
Aged 4 Weeks to 8 to 10 Weeks:
  • Zidovudine 3 mg/kg orally twice daily
Aged >8 Weeks to 10 Weeks:
  • Zidovudine 12 mg/kg orally twice daily
Note: For infants who are unable to tolerate oral agents, the intravenous 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:
  • Zidovudine 180 mg to 240 mg per m2 of body surface area every 12 hours
Adolescent (Aged ≥18 Years) and Adult Dose:
  • Zidovudine 300 mg twice daily
[Combivir and Generic] Lamivudine/Zidovudine
Child and Adolescent (Weighing ≥30 kg) and Adult Dose:
  • One tablet twice daily
[Trizivir and Generic] Abacavir/Lamivudine/Zidovudine
Child and Adolescent (Weighing ≥30 kg) and Adult Dose:
  • One tablet twice daily
  • Bone marrow suppression leading to anemia and neutropenia; macrocytosis with or without anemia.
  • 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.
  • 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
  • Zidovudine is eliminated primarily by hepatic metabolism. The major metabolite is zidovudine glucuronide, which is renally excreted.
  • Zidovudine is phosphorylated intracellularly to active zidovudine-triphosphate.
Zidovudine Dosing in Patients with Renal Impairment:
  • A zidovudine dose adjustment is required in patients with renal insufficiency.
Zidovudine Dosing in Patients with Hepatic Impairment:
  • The dose of zidovudine 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.
a For premature infants who are diagnosed with HIV infection, the time to change to the continuation dose varies with post-gestational age and clinical status of the infant.

Drug Interactions

(See also the Adult and Adolescent Antiretroviral Guidelines and HIV Drug Interaction Checker)

  • 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 neutropenia and anemia, particularly in patients with advanced HIV disease. Headache, malaise, nausea, vomiting, and anorexia. Neutropenia may occur more frequently in infants who are receiving both lamivudine and zidovudine than in infants who are 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: There is a possible increased risk of cardiomyopathy.2

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 nucleoside reverse transcriptase inhibitor (NRTI) backbone for antiretroviral therapy (ART), and it has been studied in children in combination with other NRTIs, including abacavir and lamivudine.3-19 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 the patient’s age and the results of viral resistance testing do not restrict the use of these drugs.

Efficacy in Clinical Trials
The combination of zidovudine and lamivudine has been extensively studied in children and has been a part of ART regimens in many trials. The safety and efficacy of zidovudine plus lamivudine were compared to the safety and efficacy of abacavir plus lamivudine and stavudine plus lamivudine in children aged <5 years in the CHAPAS-3 study. All regimens also included either nevirapine or efavirenz. All the NRTIs had low toxicity and produced good clinical, immunologic, and virologic responses.20 Pediatric patients who received zidovudine plus abacavir or zidovudine plus lamivudine had lower rates of viral suppression and experienced more adverse events that required regimen modification than patients who received abacavir/lamivudine.21,22

Infants with Perinatal HIV Exposure
The PACTG 076 clinical trial demonstrated that administering zidovudine to pregnant women and their infants could reduce the risk of perinatal transmission by nearly 70%.23 See Antiretroviral Management of Newborns with Perinatal HIV Exposure or Perinatal HIV for further discussion of the use of zidovudine for the prevention of perinatal transmission of HIV. A dose of approximately zidovudine 4 mg/kg of body weight every 12 hours is recommended for prevention of perinatal HIV transmission in neonates and infants with gestational ages ≥35 weeks. Infants who have been exposed to HIV but who are uninfected should continue on the prophylactic dose for 4 weeks to 6 weeks, depending on their gestational age at time of delivery and the risk assessment for perinatal transmission.

Simplified, alternative weight-band dosing has also been developed, and the rationale for these doses is based on the intracellular metabolism of zidovudine (see Pharmacokinetics below). The rate-limiting step in the 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 who received zidovudine to prevent perinatal transmission, levels of intracellular zidovudine metabolites were measured after delivery. Plasma zidovudine and intracellular zidovudine monophosphate decreased by roughly 50% between post-delivery Day 1 and Day 28, whereas zidovudine diphosphate and zidovudine triphosphate remained low throughout the sampling period.24 Zidovudine dose is poorly correlated with the active form of zidovudine found intracellularly. Because of this, a simplified weight-band dosing approach can be used for the first 4 weeks of life in infants with gestational ages ≥35 weeks (see the dosing table). 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 and will make it easier for caregivers to administer zidovudine oral syrup to their infants. The changes in weight and the small differences in zidovudine dose will have minor effects on the intracellular concentrations of zidovudine triphosphate.

Infants with HIV Infection
For full-term neonates who are diagnosed with HIV infection during the first days to weeks of life, the zidovudine dose should be increased at age 4 weeks to the continuation dose (see the dosing table). The activity of the enzymes responsible for glucuronidation is low at birth and increases dramatically during the first 4 weeks to 6 weeks of life in full-term neonates. This increase in metabolizing enzyme activity leads to an increased clearance of plasma zidovudine, and the dose of zidovudine should be adjusted when zidovudine is used to treat HIV after the first 4 weeks in full-term infants.

For premature infants who are diagnosed with HIV infection, the time to increase the zidovudine dose from the initial dose varies with post-gestational age and the clinical status of the neonate. On the basis of population pharmacokinetic (PK) modeling and simulations and data from studies that have evaluated zidovudine PK in premature infants, the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV recommends the following: in infants with HIV who were born at ≥30 weeks to <35 week switch to a dose of zidovudine 12 mg/kg twice daily at a post-gestational age of 6 weeks to 8 weeks; for infants who are born at <30 weeks, switch to zidovudine 12 mg/kg twice daily at a post-gestational age of 8 weeks to 10 weeks.25 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

Zidovudine undergoes intracellular metabolism to achieve its active form, zidovudine triphosphate. Phosphorylation requires multiple steps: zidovudine is phosphorylated by thymidine kinase to zidovudine monophosphate; zidovudine monophosphate is phosphorylated by thymidylate kinase to zidovudine diphosphate; and zidovudine diphosphate is phosphorylated by nucleoside diphosphate kinase to zidovudine triphosphate. Overall, zidovudine PKs in pediatric patients aged >3 months are similar to those seen in adults. 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.26 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 ages.4 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.15

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 plasma area under the curve values for zidovudine.3,4,27

Incidence of hematological toxicity was investigated in the ARROW study, which randomized treatment-naive Ugandan/Zimbabwean 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.28

Zidovudine is associated with greater mitochondrial toxicity than abacavir and tenofovir disoproxil fumarate, but it is associated with less mitochondrial toxicity than stavudine.29,30

While the incidence of cardiomyopathy associated with perinatal HIV infection has decreased dramatically since the use of ART became routine, the use of a regimen that contains zidovudine may increase the risk.2 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.2

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. 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.
  3. 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.
  4. 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.
  5. 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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  7. 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.
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  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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 Journal Infect Dis. 2002;34(1):41-44. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11874163.
  15. 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.
  16. 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.
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  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. 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.
  26. 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.
  27. 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.
  28. 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.
  29. 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.
  30. 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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