Lamivudine

Paul G. Auwaerter, M.D., Paul A. Pham, Pharm.D.

INDICATIONS

FDA

  • Treatment of HIV infection in combination with other antiretrovirals.
  • Treatment of HBV (Epivir HB)

NON-FDA APPROVED USES

  • Treatment of hepatitis in HIV-HBV co-infected pts.

FORMS

brand name

preparation

manufacturer

route

form

dosage^

cost*

Epivir

Lamivudine (3TC)

ViiV Healthcare

oral

tablet

150 mg, 300 mg

$7.63; $15.27

oral

solution

10 mg/mL (240 mL)

$122.14

Epivir HB (for HBV infection)

Lamivudine (3TC)Route

ViiV Healthcare

oral

tablet

100 mg

$13.66

oral

solution

5 mg/mL (240 mL)

$163.97

Combivir and generic AZT/3TC

Lamivudine (3TC)/Zidovudine (AZT)

ViiV Healthcare and generic manufacturer (Aurobindo Pharma Limited)

oral

tablet

150 mg 3TC/300 mg AZT

$16.55; generic price (TBA)

Trizivir

Lamivudine (3TC)/Zidovudine (AZT)/Abacavir (ABC)

ViiV Healthcare

oral

tablet

ABC 300 mg + AZT 300 mg + 3TC 150 mg

$26.81

Epzicom

Lamivudine (3TC)/Abacavir (ABC)

ViiV Healthcare

oral

tablet

ABC 600 mg + 3TC 300 mg

$35.78

Kivexa (brand name available in Europe)

ABC + 3TC

ViiV Healthcare

oral

tablet

ABC 600 mg + 3TC 300 mg

variable

*Prices represent cost per unit specified, are representative of "Average Wholesale Price" (AWP).
^Dosage is indicated in mg unless otherwise noted.

USUAL ADULT DOSING

  • Consider mutations present before prescribing.
  • HIV treatment: 150 mg twice daily or 300 mg once daily
    • Lamivudine, in combination with abacavir, and either efavirenz, raltegravir, boosted atazanavir, or boosted darunavir, is not recommended in patients with pretreatment HIV RNA ≥100,000 copies/mL (HHS [adult] 2019).
  • HIV post-exposure prophylaxis (off-label): start doses above within 72h of exposure in combination with other drugs.
    • Duration: 28d
  • HBV: 100 mg once daily
    • Duration is variable and influenced by HBeAg status, duration of HBV suppression, and presence of cirrhosis/decompensation. See the hepatitis B module.
    • HBV/HIV co-infection: 150 mg twice daily or 300 mg once daily, combined with tenofovir and other appropriate antiretrovirals (HHS [adult] 2019).
  • As Epivir: 3TC 300 mg PO once daily or 150 mg PO twice daily
  • As Combivir or Trizivir: 1 tab PO twice daily
  • As Epzicom: 1 tab PO once-daily

ADULT RENAL DOSING

DOSING IN HEMODIALYSIS

iHD: 50 mg x1, then 25 mg once-daily (post HD).

DOSING IN PERITONEAL DIALYSIS

50 mg x1, then 25 mg once daily

DOSING IN RENAL REPLACEMENT THERAPY

No data; consider 150 mg PO once daily.

Other Adult Renal Dosing

  • GFR 50-80 ml/min: Usual dosing.
  • Cr Clearance 30-49 mL/min: 150 mg PO daily
  • Cr Clearance 15-29 mL/min: 150 mg PO on day 1, then 100 mg once daily
  • Cr Clearance 5-14 mL/min: 150 mg PO on day 1, then 50 mg once daily
  • Cr Clearance < 5 min: 50 mg PO on day 1, then 25 once daily

PEDIATRIC DOSING

USUAL PEDIATRIC DOSING

  • Once-daily dosing is NOT recommended when initiating 3TC in infants and young children.
  • Neonate/Infant (< 4 weeks old):
    • For prevention of transmission or treatment of HIV: 2 mg/kg/dose oral solution twice daily
  • Pediatrics
    • ≥4 weeks to < 3 months:
      • 4 mg/kg/dose (max 150mg/dose) oral solution twice daily
    • ≥ 3 months weeks to < 3 years:
      • 5 mg/kg/dose (max 150mg/dose) oral solution twice daily
    • ≥ 3 years
      • 5 mg/kg/dose (max 150mg/dose) oral solution twice daily OR 10 mg/kg once daily of the oral solution (maximum 300 mg per dose)
  • Pediatric dosing for scored 150-mg tablet (weight ≥14 kg):
    • 14 to 21 kg: 1/2 tablet (75mg) twice daily
    • >21 to < 30 kg: 1/2 tablet (75mg) in AM and 1 tablet (150mg) in PM
    • ≥ 30 kg: 1 tablet (150mg) twice daily
  • Adolescent (≥ 16 y/o):
    • < 50 kg: 4 mg/kg/dose (max 150 mg) twice daily
    • ≥50 kg: 150 mg twice daily OR 300 mg once daily
  • Weight-based dosing:
    • 3 kg to < 6kg: 3 mL oral solution twice daily
    • 6 kg to < 10 kg: 4 mL oral solution twice daily
    • 10 kg to < 14kg: 6mL oral solution twice daily
  • For weight-based dosing and how to dose combination pills containing lamivudine: see the 3TC page in the Guidelines for the use of Antivirals in Pediatric HIV.
  • For HBV:
    • Children ≥2 years and Adolescents: 3 mg/kg/dose (max 100 mg/dose) once daily

PEDIATRIC RENAL DOSING

  • Infants/Children: Requires renal dosage adjustment. Insufficient data exist to recommend specific dosing; however, the following has been suggested (Aronoff 2007):
    • CrCl 30-50 mL/min: 4 mg/kg/dose once daily
    • CrCl 10-29 mL/min: 2 mg/kg/dose once daily
    • CrCl < 10 mL/min: 1 mg/kg/dose once daily
    • HD: 1 mg/kg/dose once daily, dose after HD on HD days
  • Children and Adolescents ≥30 kg:
    • CrCl ≥50 mL/min: usual dose
    • CrCl 30-49 mL/min: 150 mg once daily
    • CrCl 15-29 mL/min: 150 mg x 1, then 100 mg once daily
    • CrCl 5-14 mL/min: 150 mg x 1, then 50 mg once daily
    • CrCl < 5 mL/min: 50 mg x 1, then 25 mg once daily
    • HD: 50 mg x 1, then 25 mg once daily, dose after HD on HD days

ADVERSE DRUG REACTIONS

GENERAL

  • One of the best tolerated NRTIs with a side effect profile comparable to placebo in hepatitis trials.

OCCASIONAL

  • Headache
  • GI: nausea, diarrhea, abdominal pain
  • Insomnia (association unclear; may be due to co-administered ARVs)
  • Hepatitis flare or fulminant hepatitis (in HBV co-infected pts if 3TC withdrawn or with development 3TC-resistant HBV)

RARE

  • Lactic acidosis: listed as NRTI class effect, but unlikely to be caused by 3TC.
    • In vitro, 3TC, TDF, FTC, and ABC are not associated with mitochondrial toxicity.
  • Pancreatitis (reported in pediatric pts)

DRUG INTERACTIONS

No pertinent drug interactions since it is not a substrate, inhibitor, or inducer of CYP450 isoforms.

Drug-to-Drug Interactions

Drug

Effect of Interaction

Recommendations/Comments

Abacavir

3TC AUC decreased by 15%; Cmax decreased by 35%.

Not clinically significant. Use standard dose.

Methadone

3TC: No reported interaction. Methadone: No change.

Not clinically significant. Use standard dose.

Nelfinavir

No effect on 3TC AUC.

Not clinically significant. Use standard doses of both.

Trimethoprim/Sulfamethoxazole

3TC AUC increased by 44%.

Not clinically significant. Use standard dose.

SPECTRUM

HIV and HBV

RESISTANCE

  • 184V: selected by 3TC, resulting in high-level resistance to 3TC and FTC, a slight decrease in susceptibility to ddI and ABC, and enhanced susceptibility to AZT, d4T, and TDF.
  • TAMs (41L, 210W, 215Y/F, 219Q/E, 67N, 70R): resistance likely with multiple TAMs.
  • T69S: high-level resistance.
  • Q151M complex: high-level resistance.
  • K65R: intermediate resistance.
  • 44D and 119I: increase 3TC resistance in combination with TAMs.

PHARMACOLOGY

MECHANISM

Intracellular phosphorylation to active lamivudine triphosphate, which competitively inhibits HIV DNA polymerase.

PHARMACOKINETIC PARAMETERS

Absorption

86%

Metabolism and Excretion

Renal excretion accounts for 71%.

Protein Binding

36%

Cmax, Cmin, and AUC

Cmax = 3mcg/mL; Intracellular carbovir triphosphate 100 FM/million cells.

T1/2

Serum: 5-7 hrs; Intracellular:12 hrs.

Distribution

Widely distributed. Vd = 1.3 L/kg.

DOSING FOR DECREASED HEPATIC FUNCTION

Usual dose.

PREGNANCY RISK

Category C: Negative carcinogenicity and teratogenicity studies in rodents. Placental passage ratio of 1.0 (newborn: mother). Well tolerated in pregnant pts.

BREAST FEEDING COMPATIBILITY

Breast milk excretion in animal studies. Breastfeeding is not recommended in the U.S. to avoid post-natal transmission of HIV to a child who may not yet be infected.

COMMENTS

  • Pros: very well tolerated; active against HBV.
    • Convenient coformulations available; once-daily dosing with low pill burden (1 tab once-daily).
    • Resistance (184V mutation) increases susceptibility to AZT, d4T, and TDF and delays the accumulation of TAMs.
    • 3TC or FTC are essential components of all recommended initial regimens, coformulated with AZT (Combivir), ABC (Epzicom), and AZT + ABC (Trizivir).
    • Decreased fitness with 184V mutation, which may result in partial antiviral activity.
  • Cons: high-level resistance with a single point mutation (184V).
    • Risk of hepatitis flare or fulminant hepatitis if 3TC withdrawn or if resistance develops in co-infected pts.
    • High rate of HBV resistance with prolonged therapy if not used in combination with other anti-HBV agents (typically TDF).
    • Shorter intracellular half-life compared to FTC.
    • More frequent emergence of 184V with AZT/3TC than TDF/FTC in the GS934 study.

Basis for recommendation


  1. HIV CLINICAL GUIDELINES: ADULT AND ADOLESCENT ARV
    What to Start: Initial Combination Antiretroviral Regimens for People with HIV. https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-a... (accessed 10/28/22, last updated 9/21/22.

    Comment:
    Initial lamivudine recommendations include the following for treatment in patients without the use of long-acting cabotegravir.

    DTG plus (TAF or tenofovir disoproxil fumarate [TDF])b plus (FTC or 3TC) (AI).
    DTG/3TC (AI)—except for individuals with HIV RNA >500,000 copies/mL, HBV coinfection, or when ART is to be started before the results of HIV genotypic resistance testing for reverse transcriptase or HBV testing are available.
    For people with HIV and a history of using CAB-LA as PrEP, INSTI genotypic resistance testing should be done before starting ART. If treatment is begun before the results of genotypic testing, the following regimen is recommended: Boosted darunavir plus (TAF or TDF)b plus (FTC or 3TC)—pending the results of the genotype test (AIII).

References

  1. Castagna A, Danise A, Menzo S, et al. Lamivudine monotherapy in HIV-1-infected patients harbouring a lamivudine-resistant virus: a randomized pilot study (E-184V study). AIDS. 2006;20(6):795-803.  [PMID:16549962]

    Comment: This open-label pilot study determined whether there was a clinical or immunological benefit to continuing 3TC in pts harboring M184V mutation. Pts were randomly assigned to monotherapy with 3TC 300 mg once -daily or discontinuation of all ARV drugs (TI group). By wk 48, 20 of 29 (69%) pts in the TI group (69%) and 12 of 29 (41%) in the 3TC group had discontinued the study because of immunological (CD4 < 350) or clinical failure, which was significantly delayed in 3TC group (p = 0.018).

  2. Fox Z, Dragsted UB, Gerstoft J, et al. A randomized trial to evaluate continuation versus discontinuation of lamivudine in individuals failing a lamivudine-containing regimen: the COLATE trial. Antivir Ther. 2006;11(6):761-70.  [PMID:17310820]

    Comment: In vitro data suggest a benefit of continuing 3TC after virological failure due to a decrease in viral fitness. This prospective randomized trial did not support this theory. At wk 48, the average decline in VL (AAUCMB) was comparable between the 2 groups (p=0.65). However, continuing 3TC despite M184V mutation may be beneficial for resistance reasons, especially in pts taking AZT, d4T, or TDF. In pts who continued 3TC, 10.7 (95% CI: 7.5, 14.0) fewer nucleotide changes in viruses containing M184V (p< 0.0001) were observed.

  3. Dienstag JL, Schiff ER, Wright TL, et al. Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med. 1999;341(17):1256-63.  [PMID:10528035]

    Comment: A randomized, placebo-controlled trial in 34 centers in the U.S. with 66 untreated pts with HBV given 3TC 100 mg/day for 52 wks. Statistically significant histologic improvement with 3TC treatment (52% vs. 23%), decreased levels of HBeAg(undetectable in 32% vs. 11%), and suppression of HBV DNA (44% vs. 16%). Rate of AEs same in both groups. The limitation of 3TC monotherapy is the development of resistance, which occurs at a rate of 15-20% per yr.

  4. Perry CM, Faulds D. Lamivudine. A review of its antiviral activity, pharmacokinetic properties and therapeutic efficacy in the management of HIV infection. Drugs. 1997;53(4):657-80.  [PMID:9098665]

    Comment: Review article outlining therapeutic efficacy, pharmacokinetic properties, and antiviral activity.

  5. Panel on Antiretroviral Therapy and Medical Management of HIV-Infected Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. https://clinicalinfo.hiv.gov/en/guidelines/pediatric-arv/lamivudine (accessed 10/26/22, last updated 10/11/22) [pages O-16 to O-21]

    Comment: DHHS dosing recommendations for lamivudine in pediatric patients.

Last updated: January 14, 2023