Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs)

Actualizado
Junio 27, 2024
Reviewed
Junio 27, 2024

Lamivudine

Drug Interactions

Additional information about drug interactions is available in the Adult and Adolescent Antiretroviral Guidelines and the HIV Drug Interaction Checker(link is external).

  • Drugs that decrease renal function could decrease clearance of lamivudine (3TC).
  • Do not use 3TC in combination with emtricitabine (FTC), because these drugs have similar resistance profiles and using them together offers no additional benefit.1Do not use 3TC with fixed-dose combination (FDC) medications that contain 3TC or FTC. Please see Appendix A, Table 1. Antiretrovirals Available in Fixed-Dose Combination Tablets and refer to other sections of the Drug Appendix for drug interaction information about each individual component of FDC tablets.

Major Toxicities

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

Resistance

The International Antiviral Society–USA maintains a list of HIV drug resistance mutations(link is external), and the Stanford University HIV Drug Resistance Database(link is external) offers a discussion of each mutation.

Pediatric Use

Approval

Although 3TC is approved by the U.S. Food and Drug Administration (FDA) for the treatment of children aged ≥3 months, both the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV (the Panel) and the Panel on Treatment of HIV During Pregnancy and Prevention of Perinatal Transmission recommend the use of 3TC from birth.

Considerations for Use

The efficacy and toxicity of 3TC are equivalent to the efficacy and toxicity of FTC. The oral formulation of FTC has an advantage over the liquid formulation of 3TC because it can be given once daily at antiretroviral (ARV) initiation, whereas the liquid formulation of 3TC needs to be given twice daily at ARV initiation. When pill formulations of 3TC or FTC are used, they can be administered once daily.

Comparative Clinical Trials

Investigators studying the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort compared the efficacy of tenofovir disoproxil fumarate (TDF) plus FTC to TDF plus 3TC when these drugs were administered with a ritonavir-boosted protease inhibitor (darunavir, atazanavir, or lopinavir) in ART-naive patients.2 The adjusted hazard ratio for the virologic failure of 3TC-containing regimens compared to FTC-containing regimens within 240 weeks of starting therapy was 1.15 (95% confidence interval, 0.58–2.27). These regimens had no difference in time to virologic suppression during the first 48 weeks of therapy or time to virologic failure after attaining suppression. In a Swiss cohort, Yang et al. found a potential difference in efficacy between FTC and 3TC; however, the difference disappeared after adjusting for pill burden. Current evidence suggests that FTC and 3TC have equivalent efficacy and toxicity in ARV-naive patients.3

Efficacy

3TC has been studied in children with HIV both alone and in combination with other ARV drugs. Extensive data have demonstrated the safety of 3TC and have shown that this drug is associated with clinical improvement and virologic response. It is commonly used in children with HIV as a component of a dual nucleoside reverse transcriptase inhibitor (NRTI) backbone.4-12 In one study that evaluated the efficacy of NRTI background components, the combination of 3TC plus abacavir (ABC) was superior to zidovudine (ZDV) plus 3TC or ZDV plus ABC in achieving long-term virologic efficacy.13

Pharmacokinetics in Infants

Because of its safety profile and availability in a liquid formulation, 3TC 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 who received 3TC affirms that adjusting the dose from 3TC 2 mg/kg to 3TC 4 mg/kg every 12 hours at age 4 weeks provides optimal 3TC exposure for infants with normal maturation of renal function.14 For infants, the World Health Organization weight-band dosing (which is up to five times higher than the FDA-approved dose) results in greater plasma concentrations than the 3TC 2 mg/kg dose.15 In HIV Prevention Trials Network (HPTN) 040, 3TC was administered as a component of a three-drug regimen to prevent perinatal transmission during the first 2 weeks of life. For 2 weeks, all infants weighing >2,000 g received 3TC 6 mg twice daily, and infants weighing ≤2,000 g received 3TC 4 mg twice daily. These doses resulted in 3TC exposure that was similar to the exposure seen in infants who received the standard twice-daily dosing schedule of 3TC 2 mg/kg per dose for neonates.16

Pharmacokinetics of Liquid versus Tablet Preparations

The PKs of 3TC have been studied after either single or repeat doses in 210 pediatric subjects. Pediatric subjects who received 3TC oral solution according to the recommended dose regimen achieved plasma concentrations of 3TC that were approximately 25% lower than those of adults with HIV who received the oral solution. Pediatric subjects who received 3TC tablets achieved plasma concentrations that were comparable to or slightly higher than those observed in adults who received tablets. In pediatric subjects, the relative bioavailability of 3TC oral solution is approximately 40% lower than the relative bioavailability of tablets that contain 3TC, despite no difference in the bioavailability of these two formulations among adults. The mechanisms for the diminished relative bioavailability of 3TC oral solution are unknown,17 but results from a study in adults that compared the PKs of 3TC oral solution administered either alone or with increasing concentrations of sorbitol indicate that sorbitol decreases the total exposure of 3TC oral solution.18 Sorbitol is a component of several ARV solutions, including ABC, as well as common over-the-counter medications that may be used in infants and young children; this may explain the PK discrepancy between the oral solution and tablet formulations. Modeling of PK data in pediatric patients suggests that increasing the oral solution dose to 3TC 5 mg/kg per dose twice daily or 3TC 10 mg/kg per dose once daily (with a maximum of 3TC 300 mg administered daily) in children aged ≥3 months would provide exposures similar to those seen in adult patients who received tablet formulations. However, modeling was done with PK data derived from studies that did not use 3TC liquid formulation, and so modeling may not predict exposures for 3TC oral solution, especially when used with liquid ABC. The Panel does not recommend using a once-daily dose of 3TC until a child is aged ≥3 years. After 3 years of age, switching to once-daily dosing with the liquid formulation could be considered when harmonizing with other ARV drugs administered once daily, such as ABC and dolutegravir (DTG).

Dosing Considerations—Once-Daily versus Twice-Daily Administration

The standard adult dose for 3TC is 300 mg once daily, but data are lacking on once-daily administration of 3TC in children. Population PK data indicate that once-daily dosing of 3TC 8 mg/kg leads to area under the curve over 24 hours (AUC024h) values that are similar to those seen in patients taking 3TC 4 mg/kg twice daily, but minimum blood plasma concentration (Cmin) values are significantly lower and maximum blood plasma concentration (Cmax) values are significantly higher in children aged 1 year to 18 years.19 Intensive PKs of once-daily versus twice-daily dosing of 3TC were evaluated in children with HIV aged 2 to 13 years in the PENTA (Paediatric European Network for Treatment of AIDS) 13 trial4 and in children aged 3 months to 36 months in the PENTA 15 trial.20 Both the PENTA 13 and PENTA 15 trials used a crossover with doses of 3TC 8 mg/kg once daily or 3TC 4 mg/kg twice daily. AUC024 and clearance values were similar between these two dosing schedules, and most children maintained an undetectable HIV RNA value after the switch. An ARROW (AntiRetroviral Research fOr Watoto) trial PK study of 41 children aged 3 to 12 years (median age 7.6 years) in Uganda who were stable on twice-daily 3TC also showed equivalent AUC024h and good clinical outcomes (defined by a low disease stage and a high CD4 T lymphocyte [CD4] cell count) after switching to once-daily 3TC. Median follow-up time during this study was 1.15 years.21 The larger ARROW trial was a randomized, noninferiority trial that investigated once-daily versus twice-daily doses of 3TC in >600 pediatric patients who had initiated therapy with twice-daily 3TC and who had been receiving therapy for ≥36 weeks. Median follow-up time during the study was 114 weeks. Rates of plasma HIV RNA suppression and adverse event profiles for once-daily 3TC were similar to (and statistically noninferior to) those of twice-daily 3TC.22

All four of the studies discussed above enrolled patients who had a low plasma HIV RNA or who were clinically stable on twice-daily 3TC before switching to once-daily dosing. Therefore, the Panel supports switching from twice-daily to once-daily dosing of 3TC in children aged ≥3 years who have been clinically stable for 36 weeks with an undetectable viral load and stable CD4 count. Clinicians should use a 10 mg/kg per dose of 3TC oral solution or a weight-based dose of 3TC tablets (neither exceeding 3TC 300 mg) as part of a once-daily regimen.23 More long-term clinical trials with viral efficacy endpoints are needed to confirm that once-daily dosing of 3TC can be used effectively as part of an initial ARV regimen in children.

3TC undergoes intracellular metabolism to reach its active form, 3TC triphosphate. In adolescents, the mean half-life of intracellular 3TC triphosphate (17.7 hours) is considerably longer than that of unphosphorylated 3TC in plasma (1.5–2 hours). Intracellular concentrations of 3TC triphosphate are equivalent whether 3TC is given once daily or twice daily in adults and adolescents. This supports a recommendation for once-daily 3TC dosing based on FDA recommendations.24,25

Considerations for Use

Weight-band dosing recommendations for 3TC have been developed for children weighing ≥3 kg and receiving either the 10-mg/mL oral solution or the 150-mg scored tablets.26-28

Recent data from the IMPAACT 2019 clinical trial of dispersible and immediate-release ABC/DTG/3TC tablets in children with HIV has confirmed the FDA-approved dosing in infants and children weighing 10 to <25 kg and confirmed newly proposed dosing of this FDC (three tablets once daily of ABC 60 mg, DTG 5 mg, and 3TC 30 mg dispersed in 15–20 mL of water) in infants weighing 6 to <10 kg. ABC/DTG/3TC dispersible FDC dosing was confirmed based on PK and safety data in each weight band at the originally selected dosing, which aligned with WHO weight-band dosing for the individual ARV agents. Follow-up through 24 weeks confirmed the safety, tolerability, and virological efficacy of both formulations. The dosing guidance for infants weighing 6 to <10 kg is awaiting regulatory approval.29

Both FTC and 3TC have antiviral activity and efficacy against hepatitis B virus. For a comprehensive review of this topic, see the Hepatitis B Virus section in the Pediatric Opportunistic Infection Guidelines.

References

  1. Anderson PL, Lamba J, Aquilante CL, et al. 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: https://pubmed.ncbi.nlm.nih.gov/16791115.
  2. Rokx C, Gras L, van de Vijver D, et al. 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;17(8):571-580 Available at: https://pubmed.ncbi.nlm.nih.gov/26842457.
  3. 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: https://pubmed.ncbi.nlm.nih.gov/26362944.
  4. 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: https://pubmed.ncbi.nlm.nih.gov/15865218.
  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: https://pubmed.ncbi.nlm.nih.gov/16148846.
  6. 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: https://pubmed.ncbi.nlm.nih.gov/16371868.
  7. 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: https://pubmed.ncbi.nlm.nih.gov/11880966.
  8. 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: https://pubmed.ncbi.nlm.nih.gov/16732152.
  9. 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: https://pubmed.ncbi.nlm.nih.gov/15905735.
  10. 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: https://pubmed.ncbi.nlm.nih.gov/9835513.
  11. 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: https://pubmed.ncbi.nlm.nih.gov/10659875.
  12. Scherpbier HJ, Bekker V, van Leth F, et al. 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: https://pubmed.ncbi.nlm.nih.gov/16481448.
  13. 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: https://pubmed.ncbi.nlm.nih.gov/17457088.
  14. 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: https://pubmed.ncbi.nlm.nih.gov/17893155.
  15. 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: https://pubmed.ncbi.nlm.nih.gov/22180560.
  16. 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: https://pubmed.ncbi.nlm.nih.gov/21666540.
  17. 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
  18. Adkison K, Wolstenholme A, Lou Y, et al. Effect of sorbitol on the pharmacokinetic profile of lamivudine oral solution in adults: an open-label, randomized study. Clin Pharmacol Ther. 2018;103(3):402-408. Available at: https://pubmed.ncbi.nlm.nih.gov/29150845.
  19. 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: https://pubmed.ncbi.nlm.nih.gov/21576443.
  20. 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: https://pubmed.ncbi.nlm.nih.gov/20516550.
  21. 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: https://pubmed.ncbi.nlm.nih.gov/21149918.
  22. Musiime V, Kasirye P, Naidoo-James B, et al. Once vs. twice-daily abacavir and lamivudine in African children. AIDS. 2016;30(11):1761-1770. Available at: https://pubmed.ncbi.nlm.nih.gov/27064996.
  23. Janssen EJH, Bastiaans DET, Valitalo PAJ, et al. Dose evaluation of lamivudine in human immunodeficiency virus-infected children aged 5 months to 18 years based on a population pharmacokinetic analysis. Br J Clin Pharmacol. 2017;83(6):1287-1297. Available at: https://pubmed.ncbi.nlm.nih.gov/28079918.
  24. 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: https://pubmed.ncbi.nlm.nih.gov/14693537.
  25. 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: https://pubmed.ncbi.nlm.nih.gov/17664328.
  26. World Health Organization. Preferred antiretroviral medicines for treating and preventing HIV infection in younger children: Report of the WHO paediatric antiretroviral working group. 2008. Available at: http://apps.who.int/iris/bitstream/handle/10665/43882/9789241596619_eng.pdf;jsessionid=31285037F69DEBBDEE7C08D16ADD48F7?sequence=1(link is external)
  27. 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: https://pubmed.ncbi.nlm.nih.gov/18316996.
  28. World Health Organization. Annex 3. Dosages of ARV drugs for adults and adolescents. 2018. Available at: https://cdn.who.int/media/docs/default-source/hq-hiv-hepatitis-and-stis-library/arv_guidelines-2018-annex3a.pdf?sfvrsn=1318b82d_3(link is external)
  29. Brooks KM, Kiser JJ, Ziemba L, et al. Pharmacokinetics, safety, and tolerability of dispersible and immediate-release abacavir, dolutegravir, and lamivudine tablets in children with HIV (IMPAACT 2019): week 24 results of an open-label, multicentre, phase 1-2 dose-confirmation study. Lancet HIV. 2023;10(8):e506-e517. Available at: https://pubmed.ncbi.nlm.nih.gov/37541705.

Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs)

Actualizado
Junio 27, 2024
Reviewed
Junio 27, 2024

Lamivudine

Download Guidelines