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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Lamivudine

Last Update: April 18, 2019.

OVERVIEW

Introduction

Lamivudine is a nucleoside analogue and reverse transcriptase inhibitor used in the therapy of human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infection. Lamivudine is a very rare cause of clinically apparent drug induced liver injury, but is associated with flares of underlying hepatitis B during therapy or with abrupt withdrawal.

Background

Lamivudine (la miv' ue deen) is an L-enantiomer and substituted analogue of cytidine (2’,3’-dideoxy-3’-3-thiacytidine: 3TC) and is active against both HIV and HBV in vitro and in vivo. Lamivudine is phosphorylated intracellularly to the triphosphate which competes with the naturally occurring cytidine triphosphate for incorporation into the growing HIV or HBV DNA chain by the viral polymerase, thereby inhibiting polymerase (or reverse transcriptase) activity and causing chain termination. Lamivudine is indicated for the treatment of HBV infection as a single agent and for HIV infection in combination with other HIV medications. For HIV infection, lamivudine is available as 150 and 300 mg tablets and as oral solutions under the trade name Epivir. Lamivudine is also available in multiple fixed combinations with other antiretroviral agents such as zidovudine, abacavir, tenofovir, efavirenz, nevirapine, dolutegravir and others. The recommended dose of lamivudine for HIV infection in adults is 150 mg twice daily or 300 mg once daily. For HBV infection the recommended dose of lamivudine in adults is 100 mg orally once daily, the drug being available in this dose under the trade name Epivir-HBV. Lamivudine was approved by the FDA for HIV infection in 1995 and for HBV infection in 1998. Lamivudine is currently used in many HAART regimens but is now rarely used to treat hepatitis B because of a high rate of antiviral resistance when it is used as monotherapy as well as the availability of more potent agents with a higher barrier to resistance. Side effects of lamivudine are uncommon but may include headache, nausea, fatigue diarrhea and cough. Severe adverse events occur largely when it is withdrawn in patients with chronic hepatitis B or with the development of antiviral resistance.

Hepatotoxicity

Elevations in serum ALT levels occur in a proportion of patients with chronic hepatitis B treated with lamivudine. These elevations appear to be due to a transient flare in the underlying chronic hepatitis B and occur in three situations during and after therapy: upon initiation of therapy (treatment flares), upon development of antiviral resistance (breakthrough flares), and shortly after stopping therapy (withdrawal flares). Treatment flares typically occur during the first few months of therapy and are marked by asymptomatic elevations in serum aminotransferase levels and rarely with jaundice or symptoms (Case 1). These flares occur during the rapid decrease in HBV DNA levels with initiation of therapy. An exacerbation of hepatitis also typically occurs after development of lamivudine resistance, a few weeks or months after the initial appearance of the mutant HBV strain and rise in HBV DNA levels (Case 2). Finally, withdrawal flares occur between 4 and 12 weeks after stopping lamivudine and can be severe, symptomatic and even lead to clinical decompensation, acute liver failure and either death or need for emergency liver transplantation. Resistance and withdrawal flares typically occur as HBV DNA levels are high or rising.

Other forms of hepatotoxicity from lamivudine are extremely rare if they occur at all. Lamivudine is a rare cause of liver test abnormalities or clinically apparent liver injury in patients with HIV infection without hepatitis B. Although several instances of lactic acidosis with hepatic steatosis and liver failure have been reported in patients receiving lamivudine, in all instances other nucleoside analogues more clearly associated with mitochondrial injury [didanosine, stavudine, zalcitrabine, zidovudine] were also being taken. No convincing instances of lactic acidosis with microvesicular fat have been reported in patients with hepatitis B who typically receive lamivudine alone or in combination with adefovir or tenofovir.

Likelihood score: E (unlikely cause of clinically apparent liver injury although flares of hepatitis B can occur during or following therapy).

Mechanism of Injury

The safety of lamivudine may relate to its minimal hepatic metabolism. In addition, lamivudine is an L-enantiomer as well as being blocked at the 3’ position of the deoxyribose, thus insuring that it is not used by either nuclear or mitochondrial host polymerases. Flares during or following therapy of HBV infection probably represent immune-mediated exacerbation of hepatitis B. Finally, in vitro lamivudine has little activity against mitochondrial polymerase gamma.

Outcome and Management

Initial on-treatment flares of hepatitis B due to lamivudine are usually mild, asymptomatic and self-limited, not requiring modification of dose or discontinuation. In contrast, flares developing in association with antiviral resistance and withdrawal flares can be severe, accompanied by clinical symptoms and lead to liver decompensation and death or need for liver transplantation. For these reasons, patients who develop viral breakthrough should be followed carefully, and therapy should be replaced by or combined with an agent with a different profile of antiviral resistance. Patients who discontinue lamivudine therapy should be followed carefully and therapy reinitiated promptly if clinical symptoms or signs of severe relapse arise.

[Agents used in therapy of HBV infection include adefovir, emtricitabine, entecavir, lamivudine, telbivudine, tenofovir, interferon alfa and peginterferon.]

Drug Class: Antiviral Agents, Antiretroviral Agents, Hepatitis B Agents

Other Drugs in the Subclass, Nucleoside Analogues: Abacavir, Adefovir, Didanosine, Emtricitabine, Entecavir, Stavudine, Telbivudine, Tenofovir, Zidovudine

CASE REPORTS

Case 1. On treatment flare of hepatitis B shortly after starting lamivudine therapy.

[NIH Case: Lamivudine D6]

A 43 year old man with HBeAg-positive chronic hepatitis B was started on lamivudine (100 mg daily) and developed a mild flare in serum aminotransferase levels within a few weeks of starting therapy. He felt well and had no symptoms. He was taking no other medications or herbal products and did not drink alcohol. Physical examination was unchanged and unremarkable. Serum aminotransferase levels rose, but total bilirubin levels remained normal. A liver biopsy done before therapy had shown moderate activity and an incomplete cirrhosis (fibrosis score 5+ of a possible 6+). Lamivudine was continued at the same dose. Serum aminotransferase levels remained high for 6 weeks, but subsequently fell to near normal values. HBV DNA levels also decreased. In follow up, he remained HBeAg-positive and by 48 weeks of therapy developed antiviral resistance. He was later treated with the combination of lamivudine and adefovir with success, with loss of HBeAg and fall of HBV DNA levels to undetectable and ALT levels to normal.

Key Points

Medication:Lamivudine 100 mg daily
Pattern:Hepatocellular
Severity:1+
Latency:4 weeks
Recovery:12 weeks
Other medications:None

Laboratory Values

Time After StartingALT (U/L)AST (U/L)Bilirubin (mg/dL)HBV DNA (copies/mL)Other
0140901.12,360,000,000
2 weeks1681300.763,300,000
4 weeks2481661.14,900,000
8 weeks3072351.3170,000Alk P normal
12 weeks2021110.8
16 weeks79590.8
20 weeks53460.820,000
24 weeks62500.89,000
Normal<42<35<1.2<100

Comment

Serum ALT and AST levels doubled and rose to greater than 8 times the upper limit of the normal range during the first 3 months of antiviral therapy. However, these changes occurred while HBV DNA levels were falling, and the patient remained asymptomatic and without jaundice. Transient and asymptomatic elevations of ALT and AST above baseline are common during the first 2-12 weeks of therapy of chronic hepatitis B with virtually all nucleoside analogues. The flare is suspected to indicate a renewed immunological response to HBV, triggered by the sudden fall in HBV DNA levels and inhibition of intracellular replication. These flares may be more prominent or more significant in patients with preexisting cirrhosis, but generally do not require dose modifications or discontinuation of therapy.

Case 2. On treatment flare of hepatitis B upon development of lamivudine resistance.

[NIH Case: Lamivudine D1]

A 32 year old man was found to have abnormal liver tests when he applied for disability insurance. He was positive for hepatitis B surface and e antigen and had high serum aminotransferase and HBV DNA levels. He was minimally if at all symptomatic of liver disease, and physical examination was normal. A liver biopsy showed marked necroinflammatory activity and bridging hepatic fibrosis. He received a course of alpha interferon without a lasting response. He was then started on lamivudine (100 mg/day), whereupon serum ALT and HBV DNA levels fell promptly (Table). After 18 months, he was HBeAg-negative, but anti-HBe was not detected. After 4 years of lamivudine therapy, ALT levels were normal and repeat liver biopsy showed marked improvement. Six months later, however, while still on lamivudine, serum ALT levels began to rise and HBV DNA was again detectable in high levels. Molecular testing revealed lamivudine-resistant mutant (rtM204I) virus. He was later treated with tenofovir with prompt improvement in HBV DNA and ALT levels.

Key Points

Medication:Lamivudine 100 mg daily
Pattern:Hepatocellular
Severity:1+ (aminotransferase elevations without jaundice)
Latency:4 years
Recovery:After switching to tenofovir therapy
Other medications:None

Laboratory Values

Time After StartingALT (U/L)Bilirubin (mg/dL)HBV DNA (copies/mL)Other
05240.994,500,000Liver biopsy
1 month2101.12,430,000
2 month321.12,000
12 months271.1100
2 years200.9<100HBeAg negative
4 years200.6200Biopsy
5 years2591.1157,800,000HBeAg positive
5.5 years16571.259,800,000rtM201I mutant
5.8 years811.037,120,000
6.5 years1010.66,670,000
Lamivudine stopped and tenofovir (300 mg daily) started
7.5 years561.0None detectedStill HBeAg positive
Normal<42<1.2<100

Comment

Long term therapy of hepatitis B with lamivudine is associated with a high rate of antiviral resistance, particularly in patients with HBeAg and high levels of serum HBV DNA. Resistance usually arises in the first 2 years of therapy, but can arise at any time with long term treatment. Generally, HBV DNA levels begin to rise first, followed by increases in serum aminotransferase levels. Molecular testing shows the presence of mutations in the polymerase gene that are associated with resistance to the nucleoside analogue being used. The flare of hepatitis that accompanies development of antiviral resistance is often referred to as “breakthrough” and can be severe and even fatal, particularly in patients with preexisting, underlying cirrhosis. These features make monotherapy with lamivudine problematic in chronic hepatitis B and underscore the need to monitor patients on long term therapy carefully.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Lamivudine – Epivir®

DRUG CLASS

Antiviral Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Lamivudine134678-17-4C8-H11-N3-O3-S
Lamivudine Chemical Structure

ANNOTATED BIBLIOGRAPHY

References updated: 18 April 2019

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    (Controlled trial comparing entecavir [n=325] to lamivudine [n=313] in patients with HBeAg-negative chronic hepatitis B; on-treatment ALT elevations >5 times normal in 2% of entecavir- vs 3% of lamivudine-treated; posttreatment elevations in 12% vs 29%, no deaths from flares).
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  • Lai CL, Gane E, Liaw YF, Hsu CW, Thongsawat S, Wang Y, Chen Y, et al.; Globe Study Group. Telbivudine versus lamivudine in patients with chronic hepatitis B. N Engl J Med 2007; 357: 2576-88. [PubMed: 18094378]
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  • Soriano V, Puoti M, Garcia-Gascó Rockstroh JK, Benhamou Y, Barreiro P, McGovern B. Antiretroviral drugs and liver injury. AIDS 2008; 22: 1-13. [PubMed: 18090386]
    (Review of hepatotoxicity of antiretroviral drugs with recommendations on management, stopping therapy if symptoms arise, with overt jaundice [direct bilirubin], evidence of mitochondrial toxicity, ALT >10 times ULN, ALT at lower levels if newly marketed agent; important to rule out other causes; problematic agents include didanosine, stavudine and zidovudine, nevirapine and efavirenz, full dose ritonavir and tipranavir).
  • Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]
    (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, 7 were attributed to antiretroviral agents, 2 nevirapine, 1 efavirez and 4 miscellaneous combinations but none to lamivudine).
  • Fontana RJ. Side effects of long-term oral antiviral therapy for hepatitis B. Hepatology 2009; 49 (5 Suppl): S185-95. [PubMed: 19399802]
    (Review of side effects of nucleoside analogues used to treat chronic hepatitis B).
  • Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH, Sturkenboom MC. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol 2010; 70: 721-8. [PMC free article: PMC2997312] [PubMed: 21039766]
    (Worldwide pharmacovigilance database contained 9036 hepatic adverse drug reactions in children, 3 antiretroviral agents were among the top 40 cases, including zidovudine [8th, 106 cases], lamivudine [26th, 45 cases] and nevirapine [36th, 37 cases]).
  • Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]
    (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury and 4 to antiretroviral agents, including 3 to combinations with stavudine and 1 to abacavir, but none were attributed to lamivudine).
  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013 ; 144: 1419-25. [PubMed: 23419359]
    (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but none were attributed to lamivudine or other antivral agents used to treat hepatitis B).
  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]
    (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, two of which were attributed to lamivudine but both in combination with zidovudine to treat HIV infection).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 12 [1.3%] were attributed to antiretroviral agents but none were due to lamivudine or agents being used to treat hepatitis B).
  • Lee KS, Kweon YO, Um SH, Kim BH, Lim YS, Paik SW, Heo J, et al. Efficacy and safety of entecavir versus lamivudine over 5 years of treatment: A randomized controlled trial in Korean patients with hepatitis B e antigen-negative chronic hepatitis B. Clin Mol Hepatol 2017; 23: 331-9. [PMC free article: PMC5760004] [PubMed: 28946736]
    (Among 120 Korean patients with chronic hepatitis B treated with lamivudine or entecavir for at least 2 years, virologic responses were less common with lamivudine [48% vs 95%] while breakthough was more frequent [43% vs 1%]; serious adverse events were rare and were unrelated to therapy).
  • Pan CQ, Yi W, Liu M, Wan G, Hu YH, Zhou MF. Lamivudine therapy during the second vs the third trimester for preventing transmission of chronic hepatitis B. J Viral Hepat 2017; 24: 246-52. [PubMed: 28025872]
    (Among 160 HBsAg positive expectant mothers with high levels of HBV DNA who were treated with lamivudine starting in the 2nd or 3rd trimester of pregnancy, none had evidence of transmission of hepatitis B to their newborns, while ALT flares occurred in 3% during pregnancy and 9% postpartum when lamivudine was stopped, but none had severe hepatitis or acute liver failure).
  • Triumeq--a 3 drug combination for HIV. Med Lett Drugs Ther 2015; 57 (1459): 7-8. [PubMed: 25555073]
    (Concise review of the clinical effiacy, safety and costs of the fixed dose combination of lamivudine, abacavir and dolutegravir as a single tablet regimen for HIV infection; mentions common adverse events of insomnia, headahce and fatigue and that ALT and AST elevations can occur in patients with HBV or HCV coinfection).
  • Cahn P, Madero JS, Arribas JR, Antinori A, Ortiz R, Clarke AE, Hung CC, Et al.; GEMINI Study Team. Dolutegravir plus lamivudine versus dolutegravir plus tenofovir disoproxil fumarate and emtricitabine in antiretroviral-naive adults with HIV-1 infection (GEMINI-1 and GEMINI-2): week 48 results from two multicentre, double-blind, randomised, non-inferiority, phase 3 trials. Lancet 2019; 393 (10167): 143-55. [PubMed: 30420123]
    (Among 1441 patients with HIV infection enrolled in two controlled trials comparing 2-drug [dolutegravir and lamivudine] to 3-drug [dolutegravir, tenofovir, emtricitabine] regimens, virologic response rates were similar [91% vs 93%] while drug related adverse events were less frequent with the 2-drug regimen [18% vs 24%], but serious events were similar in frequency [1% vs 1%].

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