Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection
Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs)
Last Updated: April 27, 2017; Last Reviewed: April 27, 2017
|Lamivudine (3TC, Epivir)
For additional information see Drugs@FDA: http://www.accessdata.fda.gov/scripts/cder/daf/
|Pediatric Oral Solution: 10 mg/mL (Epivir), 5 mg/mL (Epivir HBVa)
Tablets: 150 mg (scored) and 300 mg (generic); 100 mg (Epivir HBVa)
Fixed-Dose Combination Tablets:
|Tablets: 100 mg, 150 mg, and 300 mg|
|Dosing Recommendations||Selected Adverse Events|
|Neonate and Infant Dose (Birth to <4 Weeks) for treatment:
Pediatric Dose (Aged ≥4 Weeks):
Note: The Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV (the Panel) supports consideration of switching to once-daily dosing of lamivudine from twice-daily dosing in clinically stable patients aged ≥3 years with a reasonable once-daily regimen, an undetectable viral load, and stable CD4 T lymphocyte count, at a dose of 8 to 10 mg/kg/dose to a maximum of 300 mg once daily.
Adolescent and Adult Dose
Weighing <25 kg:
Adolescent (Weighing ≥30 kg) and Adult Dose:
Adolescent (Weighing ≥40 kg)/Adult Dose:
Adolescent (Weighing ≥25 kg)/Adult Dose:
Adolescent (Weighing ≥40 kg)/Adult Dose:
|a Epivir HBV oral solution and tablets contain a lower amount of lamivudine than Epivir oral solution and tablets. The strength of lamivudine in Epivir HBV solution and tablet was based on dosing for treatment of HBV infection (in people without HIV coinfection). If Epivir HBV is used in patients with HIV, 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 lamivudine dose for treatment of HIV.|
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/)
- Renal elimination: Drugs that decrease renal function could decrease clearance of lamivudine.
- Other nucleoside reverse transcriptase inhibitors: 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.
- More common: Headache, nausea.
- Less common (more severe): Peripheral neuropathy, lipodystrophy/lipoatrophy.
- Rare: Increased liver enzymes. Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported.
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/DR/).
Lamivudine is Food and Drug Administration (FDA)-approved for the treatment of children aged ≥3 months; it is a common component of most nucleoside backbone regimens.
Considerations for Use
The efficacy and toxicity of lamivudine are equivalent to emtricitabine. Formulations favor liquid emtricitabine over liquid lamivudine, since liquid emtricitabine can be given once daily at ARV initiation but liquid lamivudine needs to be given twice daily at ARV initiation. When pill formulations can be administered, again, lamivudine and emtricitabine are equivalent.
Comparative Clinical Trials
Studies assessing the efficacy and/or potency of nucleoside/nucleotide analogues have been more concerned with the dynamic components of the regimen (e.g. tenofovir or abacavir versus the more static components [e.g. emtricitabine or lamivudine]). Emtricitabine and lamivudine have been considered interchangeable, but little data exists to make this recommendation in ARV-naive patients. Investigators in the ATHENA cohort compared naive patients who started tenofovir/emtricitabine or tenofovir/lamivudine in combination with a boosted protease inhibitor (darunavir, atazanavir, or lopinavir).2 The adjusted hazard ratio for virologic failure of lamivudine compared to emtricitabine within 240 weeks of starting therapy was 1.15 (95% CI, 0.58–2.27). There was also no difference in time to virologic suppression in the first 48 weeks of therapy or the time to virologic failure after attaining suppression. Yang et al. in the Swiss cohort found a potential difference in efficacy which disappeared after adjusting for pill burden. Current evidence suggests that emtricitabine and lamivudine are equivalent even in ARV-naive patients.3
Lamivudine has been studied in children with HIV alone and in combination with other ARV drugs. Extensive data demonstrate that lamivudine appears safe and is associated with clinical improvement and virologic response, and it is commonly used in children with HIV as a component of a dual-nucleoside reverse transcriptase inhibitor (NRTI) backbone.4-12 In 1 study, the NRTI background components of lamivudine/abacavir were superior to zidovudine/lamivudine or zidovudine/abacavir in long-term virologic efficacy.13
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.9 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.14 For infants in early life, the higher World Health Organization weight-band dosing (up to 5 times the FDA dose) results in increased plasma concentrations compared to the 2 mg/kg dosing.15 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 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.16
Pharmacokinetics of Liquid Versus Tablet Preparations
The PK of lamivudine has been studied after either single or repeat doses in 210 pediatric subjects. Pediatric subjects receiving lamivudine oral solution according to the recommended dosage regimen achieved approximately 25% lower plasma concentrations of lamivudine compared with adults with HIV receiving oral solution. Pediatric subjects receiving lamivudine oral tablets achieved plasma concentrations comparable to or slightly higher than those observed in adults receiving tablets. The relative bioavailability of lamivudine oral solution is approximately 40% lower than tablets containing lamivudine in pediatric subjects despite no difference in adults. The mechanisms for the diminished relative bioavailability of lamivudine solution are unknown,17 but a recent study in adults comparing the PK of lamivudine solution either alone or with increasing concentrations of sorbitol indicates that sorbitol decreases the total exposure of lamivudine solution.18 Sorbitol is a component of several ARV solutions used in pediatric patients, and this may explain the PK discrepancy between oral solution and tablet formulations. There are currently no studies supporting an increase in dosing for lamivudine oral solution in children.
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 ages 1 to 18 years.19 Intensive PKs of once-daily versus twice-daily dosing of lamivudine were evaluated in children with HIV aged 2 to 13 years in the PENTA-13 trial,4 and in children aged 3 to 36 months in the PENTA 15 trial.20 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.21 All 3 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 (EC) didanosine, 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.22 The patients had advanced HIV 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-EC didanosine, 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 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.
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 based upon FDA recommendations or drug co-formulations.23,24
World Health Organization Dosing
Weight-band dosing recommendations for lamivudine have been developed for children weighing at least 14 kg and receiving the 150-mg scored tablets.25,26
Both emtricitabine and lamivudine have antiviral activity and efficacy against HBV. For a comprehensive review of this topic, and hepatitis C and tuberculosis during HIV coinfection, please see the Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children.
- 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. 2006;42(4):441-449. Available at http://www.ncbi.nlm.nih.gov/pubmed/16791115.
- Rokx C, Gras L, van de Vijver D, Verbon A, Rijnders B, Study ANOC. Virological responses to lamivudine or emtricitabine when combined with tenofovir and a protease inhibitor in treatment-naive HIV-1-infected patients in the Dutch AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort. HIV Med. 2016. Available at http://www.ncbi.nlm.nih.gov/pubmed/26842457.
- Yang WL, Kouyos RD, Scherrer AU, et al. Assessing efficacy of different nucleos(t)ide backbones in NNRTI-containing regimens in the Swiss HIV Cohort Study. J Antimicrob Chemother. 2015;70(12):3323-3331. Available at http://www.ncbi.nlm.nih.gov/pubmed/26362944.
- 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.
- 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.
- 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. 2005;24(12):1072-1076. Available at http://www.ncbi.nlm.nih.gov/pubmed/16371868.
- 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. 2002;34(7):991-1001. Available at http://www.ncbi.nlm.nih.gov/pubmed/11880966.
- 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. 2006;25(6):533-537. Available at http://www.ncbi.nlm.nih.gov/pubmed/16732152.
- 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. 2005;39(2):189-194. Available at http://www.ncbi.nlm.nih.gov/pubmed/15905735.
- 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. 1998;42(12):3187-3192. Available at http://www.ncbi.nlm.nih.gov/pubmed/9835513.
- 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.
- 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. 2006;117(3):e528-536. Available at http://www.ncbi.nlm.nih.gov/pubmed/16481448.
- 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.
- Tremoulet AH, Capparelli EV, Patel P, et al. Population pharmacokinetics of lamivudine in human immunodeficiency virus-exposed and -infected infants. Antimicrob Agents Chemother. 2007;51(12):4297-4302. Available at http://www.ncbi.nlm.nih.gov/pubmed/17893155.
- Tremoulet AH, Nikanjam M, Cressey TR, et al. Developmental pharmacokinetic changes of Lamivudine in infants and children. J Clin Pharmacol. 2012;52(12):1824-1832. Available at http://www.ncbi.nlm.nih.gov/pubmed/22180560.
- Mirochnick M, Nielsen-Saines K, Pilotto JH, et al. Nelfinavir and Lamivudine pharmacokinetics during the first two weeks of life. Pediatr Infect Dis J. 2011;30(9):769-772. Available at http://www.ncbi.nlm.nih.gov/pubmed/21666540.
- Choi SY, Li F, Florian J, Seo SK. Lamivudine and abacavir clinical summary review. 2014. Available at http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM446104.pdf.
- Adkison K, Mccoig C, Wolstenholme A, et al. Effect of sorbitol on lamivudine pharmacokinetics following administration of EPIVIR® solution in adults. Presented at: Conference on Retroviruses and Opportunistic Infections. 2017. Seattle, WA.
- Bouazza N, Hirt D, Blanche S, et al. Developmental pharmacokinetics of lamivudine in 580 pediatric patients ranging from neonates to adolescents. Antimicrob Agents Chemother. 2011;55(7):3498-3504. Available at http://www.ncbi.nlm.nih.gov/pubmed/21576443.
- 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.
- 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.
- 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. 2011;89(6):451-458. Available at http://www.ncbi.nlm.nih.gov/pubmed/21673861.
- 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. 2004;48(1):176-182. Available at http://www.ncbi.nlm.nih.gov/pubmed/14693537.
- 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.
- 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.
- 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. 2008;22(5):557-565. Available at http://www.ncbi.nlm.nih.gov/pubmed/18316996.