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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs)

Lamivudine

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

Lamivudine (3TC/Epivir)
Lamivudine (3TC/Epivir)

For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm

Formulations

Oral Solution: 10 mg/mL (Epivir), 5 mg/mL (Epivir HBVa)
Tablets: 150 mg (scored) and 300 mg (generic and Epivir); 100 mg (Epivir HBVa)

Combination Tablets:
With Zidovudine:
  • 150 mg 3TC plus 300 mg zidovudine (generic and Combivir)
With Abacavir:
  • 300 mg 3TC plus 600 mg abacavir (Epzicom)
With Zidovudine and Abacavir:
  • 150 mg 3TC plus 300 mg zidovudine plus 300 mg abacavir (Trizivir)
a Epivir HBV oral solution and tablets contain a lower amount of 3TC than Epivir oral solution and tablets. The strength of 3TC in Epivir HBV solution and tablet was maximized for treatment of hepatitis B virus (HBV) only. If Epivir HBV is used in HIV-infected patients, the higher dosage indicated for HIV therapy should be used as part of an appropriate combination regimen. The Epivir HBV tablet is appropriate for use in children who require a 100 mg 3TC dose for treatment of HIV infection.

Dosing Recommendations

Neonate/Infant Dose (Aged <4 Weeks) for Prevention of Transmission or Treatment
  • 2 mg/kg twice daily
Pediatric Dose (Aged ≥4 Weeks)
  • 4 mg/kg (up to 150 mg) twice daily
Pediatric Dosing for Scored 150-mg Tablet (Weight ≥14 kg)
Weight AM dose PM Dose Total Daily Dose
14 to 21kg ½ tablet (75 mg) ½ tablet (75 mg) 150 mg
>21 to <30kg  ½ tablet (75 mg) 1 tablet (150 mg) 225 mg
≥30 kg 1 tablet (150 mg) 1 tablet (150 mg) 300 mg
       
Adolescent (Aged ≥16 Years)/Adult Dose:
Body Weight <50 kg: 
  • 4 mg/kg (up to 150 mg) twice daily
Body Weight ≥50 kg: 
  • 150 mg twice daily or 300 mg once daily
Combivir
Adolescent (Weight ≥30 kg)/Adult Dose:
  • 1 tablet twice daily
Trizivir
Adolescent (Weight >40 kg)/Adult Dose:
  • 1 tablet twice daily.
Epzicom
Adolescent (Aged >16 Years and Weight >50 kg)/Adult Dose:
  • 1 tablet once daily

Selected Adverse Events

  • Minimal toxicity
  • Exacerbation of hepatitis has been reported after discontinuation of 3TC in the setting of chronic hepatitis B infection.

Special Instructions

  • 3TC can be given without regard to food.
  • Store 3TC oral solution at room temperature.
  • Screen patients for HBV infection before administering 3TC.

Metabolism

  • Renal excretion—dosage adjustment required in renal insufficiency.
  • Combivir and Trizivir (fixed-dose combination products) should not be used in patients with creatinine clearance (CrCl) <50 mL/min, on dialysis, or with impaired hepatic function.

Drug Interactions (See also the Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents)

  • Renal elimination: Drugs that decrease renal function could decrease clearance of lamivudine.
  • Other nucleoside reverse transcriptase inhibitors (NRTIs): Do not use lamivudine in combination with emtricitabine because of the similar resistance profiles and no additive benefit.1 Do not use separately when prescribing Truvada, Atripla, Complera, or Stribild because emtricitabine is a component of these formulations. Do not use separately when prescribing Combivir, Epzicom, or Trizivir because lamivudine is already a component of these combinations.

Major Toxicities

  • More common: Headache, nausea.
  • Less common (more severe): Peripheral neuropathy, pancreatitis, lipodystrophy/lipoatrophy.
  • Rare: Increased liver enzymes. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported.

Resistance

The International Antiviral Society-USA (IAS-USA) maintains a list of updated resistance mutations (see http://www.iasusa.org/resistance_mutations/index.html) and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation (see http://hivdb.stanford.edu/pages/GRIP/3TC.html).

Pediatric Use

Approval
Lamivudine is Food and Drug Administration (FDA)-approved for use in children aged ≥3 months, and it is a common component of most nucleoside backbone regimens.

Efficacy

Lamivudine has been studied in HIV-infected children alone and in combination with other antiretroviral (ARV) drugs, and extensive data demonstrate that lamivudine appears safe and is associated with clinical improvement and virologic response.2-10 Lamivudine is commonly used in HIV-infected children as a component of a dual-NRTI backbone.3-5,7,9,10 In one study, the NRTI background components of lamivudine/abacavir were superior to zidovudine/lamivudine or zidovudine/abacavir in long-term virologic efficacy.11 

Pharmacokinetics in Infants
Because of its safety profile and availability in a liquid formulation, lamivudine has been given to infants during the first 6 weeks of life starting at a dose of 2 mg/kg every 12 hours before age 4 weeks.7 A population pharmacokinetic (PK) analysis of infants receiving lamivudine affirms that adjusting the dose of lamivudine from 2 mg/kg to 4 mg/kg every 12 hours at age 4 weeks for infants with normal maturation of renal function provides optimal lamivudine exposure.12 For infants in early life, the higher WHO weight-band dosing (up to 5 times the FDA dose) results in increased plasma concentrations compared to the 2 mg/kg dosing.13 In HPTN 040, lamivudine was given for prophylaxis of perinatal transmission in the first 2 weeks of life along with nelfinavir and 6 weeks of zidovudine according to a lower weight band dosing scheme. All infants weighing >2,000 g received 6 mg twice daily and infants weighing ≤2,000 g received 4 mg twice daily for 2 weeks. These doses resulted in lamivudine exposure similar to that seen in infants who received the standard 2 mg/kg/dose twice-daily dosing schedule for neonates.14 

Dosing Considerations—Once Daily versus Twice Daily Administration
The standard adult dosage for lamivudine is 300 mg once daily, but few data are available regarding once-daily administration of lamivudine in children. Population PK data indicate that once-daily dosing of 8 mg/kg leads to area under the curve (AUC)0-24 values similar to 4 mg/kg twice daily but Cmin values significantly lower and Cmax values significantly higher in children aged 1 to 18 years.15 Intensive PKs of once-daily versus twice-daily dosing of lamivudine were evaluated in HIV-infected children aged 2 to 13 years in the PENTA-13 trial,2 and in children 3 to 36 months of age in the PENTA 15 trial.16 Both trials were crossover design with doses of lamivudine of 8 mg/kg/once daily or 4 mg/kg/twice daily. AUC0-24 and clearance values were similar and most children maintained an undetectable plasma RNA value after the switch. A study of 41 children aged 3 to 12 years (median age 7.6 years) in Uganda who were stable on twice-daily lamivudine also showed equivalent AUC0-24 and good clinical outcome (disease stage and CD4 T lymphocyte [CD4] cell count) after a switch to once-daily lamivudine, with median follow-up of 1.15 years.17 All three studies enrolled only patients who had low viral load or were clinically stable on twice-daily lamivudine before changing to once-daily dosing. Nacro et al. studied a once-daily regimen in ARV-naive children in Burkina-Faso composed of non-enteric-coated didanosine (ddI), lamivudine, and efavirenz. Fifty-one children ranging in age from 30 months to 15 years were enrolled in this open-label, Phase II study lasting 12 months.18 The patients had advanced HIV infection with a mean CD4 percentage of 9 and median plasma RNA of 5.51 log10/copies/mL. At 12-month follow-up, 50% of patients had a plasma RNA <50 copies/mL and 80% were <300 copies/mL with marked improvements in CD4 percentage. Twenty-two percent of patients harbored multi-class-resistant viral strains. While PK values were similar to the PENTA and ARROW trials, the study was complicated by use of non-enteric-coated ddI, severe immunosuppression, and non-clade B virus. In addition, rates of virologic failure and resistance profiles were not separated by age. Therefore, the Panel supports consideration of switching to once-daily dosing of lamivudine from twice-daily dosing in clinically stable patients aged 3 years and older with a reasonable once-daily regimen, an undetectable viral load, and stable CD4 cell count, at a dose of 8 to 10 mg/kg/dose to a maximum of 300 mg once daily. More long-term clinical trials with viral efficacy endpoints are needed to confirm that once-daily dosing of lamivudine can be used effectively to initiate ARV therapy in children.

Steady-State Pharmacokinetics of Once- or Twice-Daily Lamivudine
Study/(Reference) PENTA 1524 PENTA 132 ARROW25
Location Europe Europe Uganda
N 17 14 35
Age (Years) 2 5 7
Sex (% Male) 56% 43% 42%
Race (% Black or African American) 78% Not Reported 100%
Body Weight (kg) 11 19 19
Concurrent PI Use 8 1 0
Dosing Interval (hours) 12 24 12 24 12 24
Administered Dose (mg/kg) 4.04 8.02 4.05 8.1 4.7 9.6
AUC0-24 (mg*hr/L) 9.48a 8.66a 8.88a 9.80a 11.97a 12.99a
Cmax (mg/L) 1.05a 1.87a 1.11a 2.09a 1.80a 3.17a
Cmin (mg/L) 0.08a 0.05a 0.067a 0.056a 0.08a 0.05a
Cl/F/kg (L/hr/kg) 0.79a 0.86a 0.90a 0.80a 0.79a 0.72a
a Geometric mean
Note: Data are medians except as noted.
Key to Acronyms: AUC = area under the curve; PI = protease inhibitor

Lamivudine undergoes intracellular metabolism to its active form, lamivudine triphosphate. In adolescents, the mean half-life of intracellular lamivudine triphosphate (17.7 hours) is considerably longer than that of unphosphorylated lamivudine in plasma (1.5–2 hours). Intracellular concentrations of lamivudine triphosphate have been shown to be equivalent with once- and twice-daily dosing in adults and adolescents, supporting a recommendation for once-daily lamivudine dosing in adolescents aged 16 and older who weigh 50 kg or more.19,20 

WHO Dosing
Weight-band dosing recommendations for lamivudine have been developed for children weighing at least 14 kg and receiving the 150-mg scored tablets.21,22 

Both emtricitabine and lamivudine have antiviral activity and efficacy against Hepatitis B. For a comprehensive review of this topic, and Hepatitis C and tuberculosis during HIV co-infection the reader should access the Pediatric Opportunistic Infections guidelines

References 

  1. Anderson PL, Lamba J, Aquilante CL, Schuetz E, Fletcher CV. Pharmacogenetic characteristics of indinavir, zidovudine, and lamivudine therapy in HIV-infected adults: a pilot study. J Acquir Immune Defic Syndr. Aug 1 2006;42(4):441-449. Available at http://www.ncbi.nlm.nih.gov/pubmed/16791115.
  2. Bergshoeff A, Burger D, Verweij C, et al. Plasma pharmacokinetics of once- versus twice-daily lamivudine and abacavir: simplification of combination treatment in HIV-1-infected children (PENTA-13). Antivir Ther. 2005;10(2):239-246. Available at http://www.ncbi.nlm.nih.gov/pubmed/15865218.
  3. 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. Sep 2005;24(9):793-800. Available at http://www.ncbi.nlm.nih.gov/pubmed/16148846.
  4. Chaix ML, Rouet F, Kouakoussui KA, et al. Genotypic human immunodeficiency virus type 1 drug resistance in highly active antiretroviral therapy-treated children in Abidjan, Cote d'Ivoire. Pediatr Infect Dis J. Dec 2005;24(12):1072-1076. Available at http://www.ncbi.nlm.nih.gov/pubmed/16371868.
  5. Krogstad P, Lee S, Johnson G, et al. Nucleoside-analogue reverse-transcriptase inhibitors plus nevirapine, nelfinavir, or ritonavir for pretreated children infected with human immunodeficiency virus type 1. Clin Infect Dis. Apr 1 2002;34(7):991-1001. Available at http://www.ncbi.nlm.nih.gov/pubmed/11880966.
  6. LePrevost M, Green H, Flynn J, et al. Adherence and acceptability of once daily Lamivudine and abacavir in human immunodeficiency virus type-1 infected children. Pediatr Infect Dis J. Jun 2006;25(6):533-537. Available at http://www.ncbi.nlm.nih.gov/pubmed/16732152.
  7. Mirochnick M, Stek A, Acevedo M, et al. Safety and pharmacokinetics of nelfinavir coadministered with zidovudine and lamivudine in infants during the first 6 weeks of life. J Acquir Immune Defic Syndr. Jun 1 2005;39(2):189-194. Available at http://www.ncbi.nlm.nih.gov/pubmed/15905735.
  8. Mueller BU, Lewis LL, Yuen GJ, et al. Serum and cerebrospinal fluid pharmacokinetics of intravenous and oral lamivudine in human immunodeficiency virus-infected children. Antimicrob Agents Chemother. Dec 1998;42(12):3187-3192. Available at http://www.ncbi.nlm.nih.gov/pubmed/9835513.
  9. 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. Jan 26 2000;283(4):492-498. Available at http://www.ncbi.nlm.nih.gov/pubmed/10659875.
  10. Scherpbier HJ, Bekker V, van Leth F, Jurriaans S, Lange JM, Kuijpers TW. Long-term experience with combination antiretroviral therapy that contains nelfinavir for up to 7 years in a pediatric cohort. Pediatrics. Mar 2006;117(3):e528-536. Available at http://www.ncbi.nlm.nih.gov/pubmed/16481448.
  11. 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. May 11 2007;21(8):947-955. Available at http://www.ncbi.nlm.nih.gov/pubmed/17457088.
  12. Tremoulet AH, Capparelli EV, Patel P, et al. Population pharmacokinetics of lamivudine in human immunodeficiency virus-exposed and -infected infants. Antimicrob Agents Chemother. Dec 2007;51(12):4297-4302. Available at http://www.ncbi.nlm.nih.gov/pubmed/17893155.
  13. Tremoulet AH, Nikanjam M, Cressey TR, et al. Developmental pharmacokinetic changes of Lamivudine in infants and children. J Clin Pharmacol. Dec 2012;52(12):1824-1832. Available at http://www.ncbi.nlm.nih.gov/pubmed/22180560.
  14. Mirochnick M, Nielsen-Saines K, Pilotto JH, et al. Nelfinavir and Lamivudine pharmacokinetics during the first two weeks of life. Pediatr Infect Dis J. Sep 2011;30(9):769-772. Available at http://www.ncbi.nlm.nih.gov/pubmed/21666540.
  15. Bouazza N, Hirt D, Blanche S, et al. Developmental pharmacokinetics of lamivudine in 580 pediatric patients ranging from neonates to adolescents. Antimicrob Agents Chemother. Jul 2011;55(7):3498-3504. Available at http://www.ncbi.nlm.nih.gov/pubmed/21576443.
  16. Paediatric European Network for Treatment of AIDS. Pharmacokinetic study of once-daily versus twice-daily abacavir and lamivudine in HIV type-1-infected children aged 3-<36 months. Antivir Ther. 2010;15(3):297-305. Available at http://www.ncbi.nlm.nih.gov/pubmed/20516550.
  17. Musiime V, Kendall L, Bakeera-Kitaka S, et al. Pharmacokinetics and acceptability of once- versus twice-daily lamivudine and abacavir in HIV type-1-infected Ugandan children in the ARROW Trial. Antivir Ther. 2010;15(8):1115-1124. Available at http://www.ncbi.nlm.nih.gov/pubmed/21149918.
  18. Nacro B, Zoure E, Hien H, et al. Pharmacology and immuno-virologic efficacy of once-a-day HAART in African HIV-infected children: ANRS 12103 phase II trial. Bull World Health Organ. Jun 1 2011;89(6):451-458. Available at http://www.ncbi.nlm.nih.gov/pubmed/21673861.
  19. Yuen GJ, Lou Y, Bumgarner NF, et al. Equivalent steady-state pharmacokinetics of lamivudine in plasma and lamivudine triphosphate within cells following administration of lamivudine at 300 milligrams once daily and 150 milligrams twice daily. Antimicrob Agents Chemother. Jan 2004;48(1):176-182. Available at http://www.ncbi.nlm.nih.gov/pubmed/14693537.
  20. Flynn PM, Rodman J, Lindsey JC, et al. Intracellular pharmacokinetics of once versus twice daily zidovudine and lamivudine in adolescents. Antimicrob Agents Chemother. Oct 2007;51(10):3516-3522. Available at http://www.ncbi.nlm.nih.gov/pubmed/17664328.
  21. World Health Organization (WHO). Preferred antiretroviral medicines for treating and preventing HIV infection in younger children: Report of the WHO paediatric antiretroviral working group. 2008. http://www.who.int/hiv/paediatric/Sum_WHO_ARV_Ped_ARV_dosing.pdf.
  22. L'Homme R F, Kabamba D, Ewings FM, et al. Nevirapine, stavudine and lamivudine pharmacokinetics in African children on paediatric fixed-dose combination tablets. AIDS. Mar 12 2008;22(5):557-565. Available at http://www.ncbi.nlm.nih.gov/pubmed/18316996.

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