AHFS Class:

• HIV Nucleoside and Nucleotide Reverse Transcriptase Inhibitors 8:18.08.20

Generic Name(s):

• lamiVUDine

Associated Monographs

• Antiretroviral Agents General Statement

Lamivudine, an antiretroviral agent, is a human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitor (NRTI) that is active against human immunodeficiency virus (HIV) and hepatitis B virus (HBV).1,18

Treatment of HIV Infection

Lamivudine is used in conjunction with other antiretroviral agents for the treatment of human immunodeficiency virus type 1 (HIV-1) infection in adult and pediatric patients.1,4,6,9,14,200,201

Lamivudine is commonly used as part of a dual-nucleoside reverse transcriptase inhibitor (NRTI) “backbone” of a fully suppressive antiretroviral regimen; consult guidelines for the most current information on recommended regimens.200,201,202 Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance test results, comorbid conditions, access, and cost.200,201,202

Clinical Experience

Antiretroviral-naïve Adults and Adolescents

Lamivudine has been used in dual or triple NRTI regimens that include lamivudine plus zidovudine, abacavir, and/or tenofovir.1,200,302,303

A Cochrane review of 4 randomized clinical trials (N=2247) comparing a co-formulation of lamivudine-abacavir-zidovudine to non-nucleoside reverse transcriptase inhibitors (NNRTI)- or protease inhibitor (PI)-based regimens (including efavirenz, nelfinavir, atazanavir, and ritonavir-boosted lopinavir) as initial treatment for HIV infection found no significant differences in viral suppression between lamivudine and the NNRTI- or PI-based regimens.302

Study ESS30009 was a randomized, open-label trial comparing lamivudine plus abacavir in combination with either tenofovir disoproxil fumarate (DF) or efavirenz in treatment-naïve patients.303 A total of 340 patients with a median baseline HIV-1 RNA level of 4.7 log₁₀ copies/mL and CD4+ T-cell count of 251 cells/mm³ were enrolled.303 An unplanned interim analysis of data from 194 patients with ≥8 weeks of treatment indicated a high rate of early virologic nonresponse in those receiving the triple NRTI regimen (almost 50%) versus 5% among patients given an efavirenz-containing regimen.303 After 48 weeks, 71% of patients in the efavirenz arm had HIV-1 RNA levels below 50 copies/mL.303 Based on these results, the abacavir, lamivudine, and tenofovir DF arm of the study was terminated; the ESS30009 investigators suggested that this 3-drug combination not be used.303 The most likely cause of this high rate of nonresponse was a low genetic barrier to resistance because of synergistic selection from all 3 NRTIs for 2 specific resistance mutations (M184V and K65R).303

In an open-label, pilot study, a quadruple NRTI regimen was compared with an NNRTI-based regimen of efavirenz with lamivudine and zidovudine; both regimens had similar efficacy and tolerability.121

Once-daily Versus Twice-daily Lamivudine Regimen

The comparative efficacy of a once- or twice-daily lamivudine regimen used in conjunction with zidovudine and efavirenz in an NNRTI-based regimen was evaluated in a 48-week, double-blind, double-dummy, randomized study (EPV20001) in 554 antiretroviral-naïve adults (median age 35 years, median baseline CD4+ T-cell count 362 cells/mm³ [range 69-1089/mm³], median baseline plasma HIV-1 RNA level 4.66 log₁₀ copies/mL).1,301 Patients were randomized (in a 1:1 ratio) to receive lamivudine 300 mg once daily or lamivudine 150 mg twice daily, both with matching placebos.301 All patients also received efavirenz 600 mg once daily and zidovudine 300 mg twice daily.1,301 The primary outcome was the proportion of patients achieving an HIV-1 RNA level <400 copies/mL at week 48; additional outcomes included HIV-1 RNA levels <50 copies/mL, changes in CD4+ T-cell counts, and disease progression or death.301

At 48 weeks, 67% of patients given lamivudine once daily and 65% given lamivudine twice daily achieved HIV-1 RNA levels <400 copies/mL.1 Plasma HIV-1 RNA levels were <50 copies/mL through week 48 in 61% of patients receiving the once-daily lamivudine regimen and in 63% of those receiving the twice-daily lamivudine regimen.1 At week 48, the median increase in CD4+ T-cell count was 144 cells/mm³ in those receiving the once-daily lamivudine regimen and 146 cells/mm³ in those receiving the twice-daily lamivudine regimen.1 The virologic failure rate was 8% in both groups.1 Disease progression was seen in 6 and 8% of patients in the once-daily and twice-daily lamivudine regimens, respectively.301

Antiretroviral-experienced Adults and Adolescents

Although monotherapy or 2-drug regimens that include only NRTIs are no longer recommended for treatment of HIV infection,200 early studies evaluating the safety and efficacy of lamivudine in antiretroviral-experienced (previously-treated) patients used such regimens.1,30,32,34 These studies showed that patients who received lamivudine (150 or 300 mg every 12 hours) in conjunction with zidovudine (200 mg 3 times daily) for 24 weeks experienced greater increases in CD4+ T-cell counts than those who received zidovudine monotherapy (200 mg 3 times daily) or zidovudine (200 mg 3 times daily) in conjunction with zalcitabine (0.75 mg 3 times daily; no longer commercially available in the US).30,32,34

Lamivudine was evaluated in a randomized, double-blind study (study NUCB3007; CAESAR) in 1816 HIV-infected patients (median age 36 years, median baseline CD4+ T-cell count 122 cells/mm³, 84% nucleoside-experienced, 16% treatment-naïve).1,300 Patients were randomized to lamivudine (with or without an NNRTI) or placebo added to an existing regimen (i.e., monotherapy with zidovudine [62%] or a 2-drug regimen of zidovudine plus either didanosine or zalcitabine [38%]).300 Efficacy was assessed by disease progression (a new AIDS-defining event) or death over the following 12 months.1,300

The 12-month cumulative incidence of disease progression or death was 8.9-9.6% in patients randomized to receive lamivudine (with or without an NNRTI) in conjunction with their existing regimen and 19.6% in patients randomized to receive placebo in conjunction with their existing regimen.1 The 12-month cumulative mortality was 2.6-3% in patients randomized to receive lamivudine (with or without an NNRTI) and 5.9% in patients given placebo in conjunction with their existing regimen.1

Pediatric Patients

Lamivudine is used in conjunction with other antiretrovirals, including zidovudine, abacavir, and/or dolutegravir, for the treatment of HIV-1 infection in children 3 months of age or older and weighing at least 10-40 kg.1,86,87,88,89,90,94,201,304

ACTG 300 was a randomized, double-blind trial comparing lamivudine plus zidovudine to didanosine (alone or in combination with zidovudine) in treatment-naïve HIV-1 infected pediatric patients.1,89 A total of 471 patients (median age 2.7 years [range 6 weeks to 14 years]) with a mean baseline HIV-1 RNA level of 5.0 log₁₀ copies/mL and a mean CD4+ T-cell count of 868 cells/mm³ were enrolled.1 The primary outcome was time to progression of HIV disease or death.89 Disease progression or death was seen in 6.4% of patients given lamivudine/zidovudine compared to 15.7% given didanosine at a mean duration of treatment of 9-10 months.1

The ARROW study (COL105677) was a 5-year study enrolling 1206 treatment-naïve pediatric patients (aged 3 months to 17 years) initially randomized to treatment with either lamivudine plus abacavir with an NNRTI (Group A); lamivudine, abacavir, and zidovudine plus an NNRTI for 36 weeks followed by abacavir, lamivudine and an NNRTI (Group B); or lamivudine, abacavir, and zidovudine plus an NNRTI for 36 weeks followed by lamivudine, abacavir, and zidovudine (Group C).1,305 After at least 36 weeks of treatment, eligible patients (n=669) could then be randomized to either once- or twice-daily lamivudine plus abacavir, in combination with a third antiretroviral agent.1 At 96 weeks, HIV-1 RNA levels <80 copies/mL were seen in 70 and 67% of patients in the twice- and once-daily dosing regimens, respectively.1

Clinical Perspective

Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving.200,201,202 Antiretroviral therapy (ART) is recommended for all individuals with HIV regardless of CD4 counts and should be initiated as soon as possible after diagnosis of HIV and continued indefinitely.200,201,202 The primary goals of ART are to achieve and maintain durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels) to a level below which drug-resistance mutations cannot emerge (i.e., below detectable limits), restore and preserve immunologic function, reduce HIV-related morbidity and mortality, improve quality of life, and prevent transmission of HIV.200,202 While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents, HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV, and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission, have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection.201,202,227 Because of the complexity of managing patients with HIV, it is recommended that clinicians with HIV expertise be consulted when needed.200,201,202

The use of combination antiretroviral regimens that generally include 3 drugs from 2 or more drug classes is currently recommended to achieve viral suppression.200,201 In both treatment-naïve adults and children, an initial antiretroviral regimen generally consists of 2 nucleoside reverse transcriptase inhibitors (NRTIs) administered in combination with a third active antiretroviral drug from 1 of 3 drug classes: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a protease inhibitor (PI) with a pharmacokinetic enhancer (also known as a booster; the 2 drugs used for this purpose are cobicistat and ritonavir).200,201,202 Selection of an initial antiretroviral regimen should be individualized based on factors such as virologic efficacy, toxicity, pill burden, dosing frequency, drug-drug interaction potential, resistance test results, comorbid conditions, access, and cost.200,201,202 In patients with comorbid infections (e.g., hepatitis B, tuberculosis), antiretroviral regimen selection should also consider the potential for activity against other present infections and timing of initiation relative to other anti-infective regimens.200

Lamivudine, an NRTI, is commonly used as part of a dual-NRTI “backbone” of a fully suppressive antiretroviral regimen.200 In the 2023 HHS adult and adolescent HIV treatment guideline, lamivudine is included in various regimens.200 Some of these lamivudine-containing regimens are listed among recommended initial regimens in certain clinical situations, and include the following: dolutegravir/lamivudine (except for HIV-1 RNA >500,000 copies/mL, chronic HBV coinfection, or before HIV genotypic resistance testing results are available), dolutegravir/abacavir/lamivudine (only in patients who are negative for human leukocyte antigen [HLA-B*5701] and without HBV coinfection), dolutegravir/tenofovir (alafenamide [TAF] or disoproxil fumarate [TDF])/lamivudine, and boosted darunavir/tenofovir (TAF or TDF)/lamivudine for individuals with prior exposure to cabotegravir pending results of INSTI genotypic testing.200

In the 2023 HHS pediatric HIV treatment guideline, lamivudine is included in various antiretroviral regimens.201 Lamivudine is recommended as part of a preferred dual-NRTI combination for initial therapy in neonates aged birth to 1 month and includes the following regimens: abacavir/lamivudine and zidovudine/lamivudine.201 For pediatric patients aged >1 month to <2 years, abacavir/lamivudine is a preferred regimen as initial therapy.201 For patients ≥2 years of age, preferred regimens include abacavir/lamivudine.201 Lamivudine is also included in alternative dual-NRTI “backbone" regimens for pediatric patients (infants ≥1 month to children aged 12 years).201

Prevention of Perinatal HIV Transmission

Clinical Experience

Lamivudine is used in conjunction with other antiretrovirals for empiric HIV+ therapy†in neonates for prevention of perinatal HIV transmission†202 Lamivudine in combination with zidovudine for prevention of maternal-infant HIV-1 transmission was evaluated in an open-label, nonrandomized trial.93 Lamivudine was initiated at 32 weeks gestation in 445 HIV+ pregnant women, along with standard zidovudine.93 The HIV-1 maternal-infant transmission rate with lamivudine plus zidovudine was 1.6%, a 5-fold lower rate compared to zidovudine alone.93

Clinical Perspective

In the 2023 HHS perinatal HIV treatment guideline, lamividine is included in various antiretroviral regimens as part of a dual-NRTI “backbone.”202 Some of these lamivudine-containing regimens are listed among preferred options for antiretroviral-naïve patients during pregnancy and include the following: lamivudine plus abacavir; tenofovir alafenamide plus either emtricitabine or lamivudine; and tenofovir DF plus lamivudine.202 Additionally, lamivudine is included as part of a preferred INSTI regimen and a preferred PI regimen for initial therapy during pregnancy and as part of alternate NRTI and NNRTI regimens.202 For treatment-experienced patients during and prior to pregnancy, lamivudine is included as a preferred agent in various regimens.202

The choice of a neonatal antiretroviral prophylaxis regimen or a neonatal empiric HIV therapy† regimen should be based on an assessment of the likelihood of perinatal HIV transmission.202 In the 2023 HHS perinatal HIV treatment guideline, lamivudine is included in a 3-drug regimen for neonates at high risk for perinatal HIV acquisition: zidovudine (for 6 weeks), lamivudine, and either nevirapine or raltegravir (each for 2-6 weeks).202

Postexposure Prophylaxis following Occupational Exposure to HIV

Lamivudine is used as an alternative regimen in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in healthcare personnel and other individuals.199

Clinical Perspective

The US Public Health Service (USPHS) states that the preferred regimen for PEP following occupational exposure to HIV is a 3-drug regimen of raltegravir used in conjunction with emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®).199 These experts recommend several alternative regimens that include an INSTI, NNRTI, or PI and 2 NRTIs (dual NRTIs).199 The preferred dual NRTI option for use in PEP regimens is emtricitabine and tenofovir DF (may be administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®); alternative dual NRTIs are tenofovir DF and lamivudine, lamivudine and zidovudine (may be administered as the fixed combination lamivudine/zidovudine; Combivir^®), or zidovudine and emtricitabine.199

Because management of occupational exposures to HIV is complex and evolving, consultation with an infectious disease specialist, a clinician with expertise in the administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended whenever possible.199 However, initiation of PEP should not be delayed while waiting for expert consultation.199

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

Lamivudine is used in conjunction with other antiretrovirals for postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP) after sexual, injection drug use, or other nonoccupational exposures.198

Clinical Perspective

When nPEP is indicated following a nonoccupational exposure to HIV, the US Centers for Disease Control and Prevention (CDC) states that the preferred regimen in adults and adolescents 13 years of age or older with normal renal function is either raltegravir or dolutegravir used in conjunction with emtricitabine and tenofovir DF (administered as the fixed combination emtricitabine/tenofovir DF; Truvada^®).198 Lamivudine is included as an alternative agent in conjunction with other antiretroviral agents for patients aged ≥13 years with renal dysfunction and in pediatric patients aged 2-12 years.198

Consultation with an infectious disease specialist, clinician with expertise in the administration of antiretroviral agents, and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline at 888-448-4911) is recommended if nPEP is indicated in certain exposed individuals (e.g., pregnant women, children, those with medical conditions such as renal impairment), or if an antiretroviral regimen not included in the CDC guidelines is being considered, the source virus is known or likely to be resistant to antiretrovirals, or the healthcare provider is inexperienced in prescribing antiretrovirals.198 However, initiation of nPEP should not be delayed while waiting for expert consultation.198

Chronic Hepatitis B Virus Infection

Lamivudine is used for the treatment of chronic hepatitis B virus (HBV) infection associated with evidence of HBV replication and active liver inflammation.18,65,67,68,69,70,71,72,73,74,75,97,98

Guidelines from the American Association for the Study of Liver Diseases (AASLD) state that lamivudine is not considered a preferred antiviral for treatment of chronic HBV infection because a high rate of lamivudine-resistant HBV has been reported.97,98,309 The manufacturer states that lamivudine should be considered for the treatment of chronic HBV infection only when alternative antiviral agents associated with a higher genetic barrier to resistance are not available or appropriate.18

Clinical Experience

Adults

Safety and efficacy of lamivudine for treatment of HBV infection were evaluated in 3 controlled studies in patients 16 years of age or older with compensated chronic HBV infection (serum HBsAg positive for at least 6 months) accompanied by evidence of HBV replication (positive for serum HBeAg and positive for serum HBV DNA as measured by a research solution hybridization assay) and persistently elevated serum ALT concentrations and/or chronic inflammation on liver biopsy compatible with a diagnosis of chronic viral hepatitis.18,69,306,307

Trial 1 was a randomized, double-blind, placebo-controlled trial enrolling 143 previously untreated adult patients with chronic HBV.307 Patients were treated with lamivudine 100 mg or placebo for 52 weeks, with a primary outcome of improvement in Histologic Activity Index (HAI) score of at least 2 points.307 Secondary outcomes included the appearance of antibodies to HBeAg (seroconversion).307 Histologic improvement occurred in 55% of patients given lamivudine and in 25% of placebo-treated patients.18 Seroconversion occurred in 17 and 6% of patients in the lamivudine and placebo groups, respectively.18 Histologic response was seen in 56 and 25% of patients treated with lamivudine 100 mg and placebo, respectively.18,307

Trial 2, a randomized, double-blind trial, enrolled 358 adults in China with chronic HBV who were randomized to treatment with lamivudine 25 mg, lamivudine 100 mg, or placebo once daily for 12 months.18,69 The primary endpoint was a reduction in Knodell necroinflammatory score by at least 2 points (histologic response); secondary endpoints included HBeAg seroconversion.69 Hepatic necroinflammatory activity improved in 56, 49, and 25% and deteriorated in 7, 8, and 26% of patients in the lamivudine 100 mg, 25 mg, and placebo groups, respectively.69 Therapy with lamivudine 100 mg daily was associated with a reduction in the progression of hepatic fibrosis compared with placebo.69 At 12 months, HBeAg seroconversion occurred in 16, 13, and 4% of patients receiving lamivudine 100 mg daily, 25 mg daily, and placebo, respectively.69 Therapy with lamivudine 100 mg daily was associated with a rapid and sustained reduction in HBV DNA (97% reduction at week 2, 98% reduction at week 52 compared with baseline) and sustained serum ALT response in 72% of patients; therapy with lamivudine 25 mg daily or placebo was associated with a 93 or 54% reduction in HBV DNA at week 52 and sustained ALT response in 65 or 24% of patients, respectively.69 In this study, therapy with lamivudine 100 mg daily was more effective than lamivudine 25 mg daily or placebo.69

Trial 3 was a randomized, partially blinded trial with 238 adult patients randomly assigned to treatment with lamivudine 100 mg once daily for 52 weeks, placebo once daily for 52 weeks, or a regimen with lamivudine and interferon alpha-2b for 24 weeks.306 Histologic response, based on a reduction in HAI scores of ≥2 was the primary outcome; seroconversion was included in the secondary outcomes.18,306 Histologic response occurred in 52 or 25% of patients treated with lamivudine for 52 weeks or placebo, respectively.306 Seroconversion at 68 weeks occurred in 15 or 13% of patients treated with lamivudine or placebo, respectively.18 For the combination group, histologic response and seroconversion occurred in 32 and 9% of patients treated with lamivudine or placebo, respectively.306

While therapy with lamivudine is associated with histologic improvement in most patients and is well tolerated, the optimum duration of therapy, the durability of HBeAg seroconversions occurring during treatment, and the relationship between treatment response and long-term outcomes such as hepatocellular carcinoma or decompensated cirrhosis remain to be determined.18,76 There is some evidence that the efficacy of lamivudine may not be sustained during continued therapy.18,69,76 Results from 52-week studies in adults indicate that HBV DNA levels decrease to below the limits of detection in the majority of lamivudine-treated patients early in the course of treatment; however, assay-detectable HBV DNA reappears during treatment in approximately one-third of those who had an initial response.18 Strains of HBV with resistance to lamivudine have emerged during therapy with the drug, especially during long-term treatment.18,69,73 Development of lamivudine-resistant HBV during treatment with the drug has been associated with decreased treatment responses evidenced by lower rates of HBeAg seroconversion and HBeAg loss and more frequent increases in HBV DNA levels and serum ALT concentrations after an initial response.18,69 Progression of HBV infection, including death, has been reported in some patients with lamivudine-resistant HBV.18

Pediatric Patients

Lamivudine is used for the treatment of chronic HBV infection in children 2 years of age or older.18 Safety and efficacy of lamivudine were evaluated in a randomized, placebo-controlled, double-blind clinical study in 286 children and adolescents 2-17 years of age with compensated chronic HBV infection accompanied by evidence of HBV replication (positive serum HBeAg and positive for serum HBV DNA as measured by a research branched DNA [bDNA] assay) and persistently elevated serum ALT concentrations.18,308 Loss of HBeAg and reduction of HBV DNA to below the limits of detection of the research assay (evaluated at week 52) occurred in 23% of children who received 52 weeks of lamivudine (3 mg/kg once daily; maximum 100 mg once daily) compared with 13% of those who received placebo.18 In addition, normalization of serum ALT concentrations was achieved and maintained to week 52 more frequently in patients treated with lamivudine (55%) compared with placebo (12%).18,308 As in the controlled studies in adults, most lamivudine-treated pediatric patients had decreases in serum HBV DNA concentrations below the limits of detection early in treatment, but about one-third of subjects with this initial response had reappearance of detectable HBV DNA during treatment.18 Adolescents (13-17 years of age) showed less evidence of this treatment effect than younger children.18,95

HIV-infected Patients

Safety and efficacy of lamivudine for treatment of chronic HBV infection in patients coinfected with HIV † have not been established.18

HIV-infected patients coinfected with HBV often have higher HBV viral loads and are more likely to have detectable HBeAg, lower rates of HBeAg seroconversion, and an increased risk for and more rapid progression to cirrhosis, end-stage liver disease, and/or hepatocellular carcinoma compared with individuals not infected with HIV.98,155,156,200 Decisions to initiate HBV treatment in patients coinfected with HIV and HBV and the most appropriate drugs for HBV treatment in such patients depend on various factors, including the possible effects on replication of both HIV and HBV and whether the patient is currently receiving antiretroviral therapy.97,155,156,200

Although lamivudine is active against both HBV and HIV, it should not be used for treatment of chronic HBV infection in HIV-infected individuals who are not currently receiving antiretroviral therapy since dosages used for treatment of HBV infection are lower than those recommended for treatment of HIV infection and use of suboptimal dosages in HIV-infected individuals may allow for the selection of lamivudine-resistant HIV.18,155,156,200 In addition, the emergence of lamivudine-resistant HBV has been reported in HIV-infected individuals who were coinfected with HBV and receiving lamivudine-containing antiretroviral regimens.1,31,41,100,101,155,227 Although a high rate of emergence of lamivudine-resistant HBV has been reported with long-term lamivudine therapy in HBV-infected patients without HIV infection, there is some evidence to suggest that the rate of emergence of HBV resistance may be even higher in HIV-infected individuals who receive the drug.155 Reactivation of chronic HBV has been reported in HIV-infected patients who received long-term lamivudine therapy,1,47 and fulminant and fatal reactivation of chronic HBV infection as the result of emergence of lamivudine-resistant HBV has been reported.47

Clinical Perspective

The 2018 Hepatitis B Practice Guidance from AASLD identifies preferred approaches to the diagnosis and treatment of chronic HBV.309 Patients testing positive on screening tests require additional testing and management of HBV.309 Antiviral therapies for HBV include a number of agents; preferred agents include interferons, entecavir, tenofovir DF, and tenofovir alafenamide.309 Lamivudine, adefovir, and telbivudine are nonpreferred agents for HBV.309 Treatment of patients who are HBsAg-positive depends on a number of factors, including ALT levels, hepatitis B e-antigen (HBeAg) status, and HBV DNA viral load.309

Patients with HBV and HIV coinfection should be treated with antiretroviral therapy, with the regimen including 2 drugs with activity against HBV (a “backbone” regimen of TDF or TAF plus lamivudine or emtricitabine).309

General

Pretreatment Screening

• When lamivudine is used for treatment of hepatitis B virus (HBV), offer human immunodeficiency virus (HIV) testing prior to starting therapy.18

Patient Monitoring

• When lamivudine is used for treatment of HBV, offer HIV testing periodically during therapy.18
• Closely monitor for exacerbation of hepatitis in patients with HBV and HIV-1 coinfection for at least several months after stopping lamivudine treatment.1,18
• Consider more frequent monitoring of HBV viral load when chronic coadministration of sorbitol-containing products cannot be avoided.18

Dispensing and Administration Precautions

• Lamivudine is commercially available as a single entity and in various fixed-combination preparations containing additional antiretroviral agents.227,228,229,240,310,311,312,313,314 Refer to the full prescribing information for specific, distinct uses of the combination products. Since the antiretroviral agents contained in the fixed combination preparations also may be available in single-entity or other fixed-combination preparations, exercise care to ensure that therapy is not duplicated if a fixed combination is used in conjunction with other antiretrovirals.227,228,229,240,310,311,312,313,314

Administration

Lamivudine is administered orally once or twice daily without regard to meals.1,18

For the treatment of HIV-1 infection, lamivudine is commercially available as an oral solution containing 10 mg/mL or tablets containing 150 or 300 mg of the drug (Epivir^®, generic).1 The 150-mg scored tablets are the preferred preparation in pediatric patients who weigh 14 kg or more and can swallow tablets.1 The oral solution should be used in those unable to safely and reliably swallow tablets.1 Lamivudine is used in conjunction with other antiretrovirals for the treatment of HIV-1 infection.1

For the treatment of chronic HBV infection, lamivudine is commercially available as an oral solution containing 5 mg/mL or film-coated tablets containing 100 mg of the drug (Epivir-HBV^®, generic).18 The 5-mg/mL oral solution should be used in patients requiring a dosage less than 100 mg and in children unable to reliably swallow tablets.18

Lamivudine preparations labeled by FDA for treatment of chronic HBV infection should not be used in HIV-infected patients because they contain a lower dosage of the drug than that required for treatment of HIV-1 infection.1,18 If such preparations are used for the management of chronic HBV infection in a patient with unrecognized or untreated HIV infection, rapid emergence of HIV resistance is likely to result because of the subtherapeutic dose and the inappropriateness of monotherapy for HIV-infected individuals.18

Store lamivudine 100-mg, 150-mg, and 300-mg tablets at 25°C (excursions permitted between 15-30°C).1,18 Store lamivudine 5-mg/mL oral solution at 20-25°C and store lamivudine 10-mg/mL oral solution at 25°C.1,18

Fixed Combinations Containing Lamivuidine

Lamivudine is also commercially available in the following fixed-combination preparations for oral use: lamivudine/zidovudine (Combivir^®, generic)227 , abacavir/lamivudine (Epzicom^®, generic)228 , abacavir/lamivudine/zidovudine (Trizivir^®, generic)229 , lamivudine/tenofovir disoproxil fumarate (Cimduo^®)310 , doravirine/lamivudine/tenofovir disoproxil fumarate (Delstrigo^®)311 , dolutegravir/lamivudine (Dovato^®)312 , efavirenz/lamivudine/tenofovir disoproxil fumarate (Symfi^®; Symfi^® Lo)313,314 , and abacavir/dolutegravir/lamivudine (Triumeq^®; Triumeq PD^®).240 See the full prescribing information for administration of each of these combination products.227,228,229,240,310,311,312,313,314

Dosage

Treatment of HIV Infection

Adult Dosage

The usual dosage of lamivudine for the treatment of HIV-1 infection in adults is 150 mg twice daily or 300 mg once daily.1

Pediatric Dosage

When lamivudine oral solution containing 10 mg/mL is used for the treatment of HIV-1 infection in pediatric patients 3 months of age or older, the recommended dosage is 5 mg/kg twice daily or 10 mg/kg once daily (up to 300 mg maximum daily dosage).1 Consider HIV-1 viral load and CD4+ cell count/percentage when selecting the dosing interval for patients initiating treatment with oral solution.1

When lamivudine 150-mg scored tablets are used in pediatric patients 3 months of age or older who weigh 14 kg or more and are able to swallow tablets, the recommended dosage is based on weight (see Table 1and Table 2).1 Data regarding efficacy of the once-daily regimen of lamivudine given as 150-mg scored tablets in pediatric patients 3 months of age or older is limited to those who transitioned from a twice-daily regimen to a once-daily regimen after 36 weeks of treatment.1

Although safety and efficacy of lamivudine in infants younger than 3 months of age have not been established,1 some experts suggest that neonates younger than 4 weeks of age† can receive lamivudine in a dosage of 2 mg/kg twice daily and infants 4 weeks of age or older† can receive a dosage of 4 mg/kg (up to 150 mg) twice daily.201

Prevention of Perinatal Transmission

Pediatric Dosage

When empiric HIV therapy† is used for prevention of perinatal HIV transmission † in neonates at highest risk of HIV acquisition, a 3-drug antiretroviral regimen of zidovudine, lamivudine, and nevirapine is recommended and should be initiated as soon as possible after birth (within 6-12 hours).202

For empiric HIV therapy† in HIV-exposed neonates, experts recommend that lamivudine be given in a dosage of 2 mg/kg twice daily from birth to 4 weeks of age followed by 4 mg/kg twice daily from 4-6 weeks of age.202

The optimal duration of empiric HIV therapy† in HIV-exposed neonates at highest risk of HIV acquisition is unknown.202 Many experts recommend that the 3-drug regimen be continued for 6 weeks; others discontinue nevirapine and/or lamivudine if the result of the neonate's HIV nucleic acid amplification test (NAAT) is negative, but recommend continuing zidovudine for 6 weeks.202

Clinicians can consult the National Perinatal HIV Hotline at 888-448-8765 for information regarding selection of antiretrovirals, including dosage considerations, for the prevention of perinatal HIV transmission.202

Postexposure Prophylaxis following Occupational Exposure to HIV

For postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel or other individuals, the preferred dosage of lamivudine is 300 mg once daily.199 Alternatively, lamivudine can be given in a dosage of 150 mg twice daily.199 Lamivudine is usually used with tenofovir DF or zidovudine in conjunction with a recommended HIV integrase strand transferase inhibitor (INSTI), HIV nonnucleoside reverse transcriptase inhibitor (NNRTI), or HIV protease inhibitor (PI).199

PEP should be initiated as soon as possible following occupational exposure to HIV (preferably within hours) and continued for 4 weeks if tolerated.199

Postexposure Prophylaxis following Nonoccupational Exposure to HIV

For postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP) in adults and adolescents ≥13 years of age with impaired renal function (creatinine clearance 59 mL/minute or less), lamivudine is usually used in conjunction with another HIV nucleoside reverse transcriptase inhibitor (NRTI; zidovudine) in addition to another recommended agent (either an INSTI, PI, or NNRTI).198 Lamivudine dosage should be adjusted based on the degree of renal impairment.198

The nPEP regimen should be initiated as soon as possible (within 72 hours) following nonoccupational exposure to HIV and continued for 28 days.198 If it has been more than 72 hours since the exposure, nPEP is not recommended.198

Chronic Hepatitis B Virus Infection

Prior to and periodically during lamivudine therapy for the treatment of chronic HBV infection, the HIV status of the patient should be determined since the dosage of the drug used for the treatment of HBV infection is lower than the dosage used for the treatment of HIV infection and use of suboptimal dosages in HIV-infected individuals may allow for the selection of lamivudine-resistant HIV isolates.18

The optimum duration of lamivudine therapy for the treatment of chronic HBV infection is not known.18

Patients receiving lamivudine for the treatment of chronic HBV infection should be monitored regularly by a clinician experienced in the management of chronic HBV infection.18 During lamivudine therapy, events that may be considered as potentially reflecting loss of therapeutic response include combinations of such events as return of persistently elevated serum ALT concentrations, increasing levels of HBV DNA over time after an initial decline below the limits of detection of the assay, progression of clinical signs or symptoms of hepatic disease, and/or worsening of hepatic necroinflammatory findings.18 Such events should be taken into consideration when determining the advisability of continuing lamivudine therapy.18

Adult Dosage

When lamivudine (100-mg tablets or oral solution containing 5 mg/mL) is used for the treatment of chronic HBV infection in adults, the recommended dosage is 100 mg once daily.18

Pediatric Dosage

The recommended oral dosage of lamivudine for pediatric patients 2-17 years of age is 3 mg/kg once daily up to a maximum daily dosage of 100 mg.18 The oral solution formulation should be prescribed for patients requiring a dosage less than 100 mg or if unable to swallow tablets.18

Special Populations

Hepatic Impairment

Because lamivudine pharmacokinetics are not affected by hepatic impairment, dosage adjustments are not necessary.1,18 However, safety and efficacy have not been established in those with decompensated liver disease.1,18

Renal Impairment

Because the elimination of lamivudine may be reduced in patients with renal impairment, dosage of the drug should be decreased in those with a creatinine clearance less than 50 mL/minute.1 If lamivudine is used for the treatment of HIV infection in adults and adolescents weighing 25 kg or more with impaired renal function, dosage of the drug should be adjusted based on creatinine clearance (See Table 3).1 The manufacturer states that data are insufficient to make dosage recommendations for HIV-infected pediatric patients with renal impairment; however, a reduction in the dose and/or an increase in the dosing interval should be considered.1

If lamivudine is used for treatment of chronic HBV infection in adults with impaired renal function, dosage of the drug should be adjusted based on creatinine clearance (See Table 4).18 The manufacturer states that data are insufficient to make specific dosage recommendations for pediatric patients with renal impairment.18

Geriatric Patients

Use with caution in geriatric patients because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.1,18

Contraindications

• Previous hypersensitivity to lamivudine.1,18

Warnings/Precautions

Warnings

Patients with Hepatitis B Virus and HIV-1 Coinfection

The prescribing information of lamivudine contains a boxed warning regarding the risk of severe acute exacerbations of hepatitis B in patients who are coinfected with hepatitis B virus (HBV) and HIV-1 and have discontinued lamivudine.1,18 Monitor hepatic function closely in these patients, and if appropriate, initiate anti-hepatitis B treatment.1,18 Clinical and laboratory evidence of exacerbations of hepatitis have occurred after discontinuation of lamivudine.1,18 These exacerbations have been detected primarily by serum ALT elevations in addition to the re-emergence of HBV DNA.1,18 Although most events appear to have been self-limited, fatalities have been reported.1,18 Similar events have been reported from postmarketing experience after changes from lamivudine-containing HIV-1 treatment regimens to non-lamivudine-containing regimens in patients infected with both HIV-1 and HBV.1 The causal relationship to discontinuation of lamivudine treatment is unknown.1,18 Monitor patients closely with both clinical and laboratory follow-up for at least several months after stopping treatment.1,18 Safety and efficacy of lamivudine have not been established for the treatment of chronic hepatitis B in subjects dually infected with HIV-1 and HBV.1,18 Emergence of HBV variants associated with resistance to lamivudine has also been reported in HIV-1-infected subjects who have received lamivudine-containing antiretroviral regimens in the presence of concurrent infection with HBV.1

Differences Between Lamivudine Preparations and Risk of HIV-1 Resistance in Patients with Unrecognized or Untreated HIV-1 Infection

Boxed warnings about the different formulations of lamivudine and the risk of HIV-1 resistance in patients with unrecognized or untreated HIV-1 infection are included in the prescribing information for lamivudine.1,18 Epivir-HBV^® tablets and oral solution contain a lower lamivudine dose than the lamivudine dosage used to treat HIV-1 infection with Epivir^® tablets and oral solution or with lamivudine-containing antiretroviral fixed-dose combination products.1,18 Epivir-HBV^® is not appropriate for patients co-infected with HBV and HIV-1.1,18 If a patient with unrecognized or untreated HIV-1 infection is prescribed Epivir-HBV^® for the treatment of HBV, rapid emergence of HIV-1 resistance is likely to result because of the subtherapeutic dose and the inappropriate use of monotherapy for HIV-1 treatment.1,18 Offer HIV counseling and testing to all patients before beginning treatment with Epivir-HBV^® and periodically during treatment because of the risk of rapid emergence of resistant HIV-1 and the limitation of treatment options if Epivir-HBV^® is prescribed to treat chronic hepatitis B in a patient who has unrecognized or untreated HIV-1 infection or who acquires HIV-1 infection during treatment.18

Other Warnings/Precautions

Lactic Acidosis and Severe Hepatomegaly with Steatosis

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues, including lamivudine.1,18 A majority of these cases have been in women; female sex and obesity may be risk factors in patients treated with antiretroviral nucleoside analogues.1,18 Most of these reports have described patients receiving nucleoside analogues for treatment of HIV infection, but there have been reports of lactic acidosis in patients receiving lamivudine for hepatitis B.18 Suspend treatment with lamivudine in any patient who develops clinical or laboratory findings suggestive of lactic acidosis or pronounced hepatotoxicity, which may include hepatomegaly and steatosis, even in the absence of marked transaminase elevations.1,18

Pancreatitis

Use lamivudine with caution in pediatric patients with a history of prior antiretroviral nucleoside exposure, a history of pancreatitis, or other significant risk factors for the development of pancreatitis.1 Discontinue treatment with lamivudine immediately if clinical signs, symptoms, or laboratory abnormalities suggestive of pancreatitis occur.1

Immune Reconstitution Syndrome

Immune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including lamivudine.1 During the initial phase of combination antiretroviral treatment, patients whose immune systems respond may develop an inflammatory response to indolent or residual opportunistic infections (e.g., Mycobacterium avium complex infection, cytomegalovirus, Pneumocystis jirovecii pneumonia [PCP], or tuberculosis); this may necessitate further evaluation and treatment.1 Autoimmune disorders (e.g., Graves' disease, polymyositis, Guillain-Barré syndrome) have also been reported in the setting of immune reconstitution; however, the time to onset is more variable and can occur many months after initiation of treatment.1

Lower Virologic Suppression Rates and Increased Risk of Viral Resistance with Oral Solution

Pediatric subjects who received lamivudine oral solution (Epivir^®; at weight band-based doses approximating 8 mg/kg per day) along with other antiretroviral oral solutions at any time during the ARROW trial had lower rates of virologic suppression, lower plasma lamivudine exposure, and developed viral resistance more frequently than those receiving Epivir^® tablets.1 Epivir^® scored tablet is the preferred formulation for HIV-1-infected pediatric patients who weigh at least 14 kg and for whom a solid dosage form is appropriate.1 An all-tablet regimen should be used when possible to avoid a potential interaction with sorbitol.1 Consider more frequent monitoring of HIV-1 viral load when using Epivir^® oral solution.1

Emergence of Resistance-Associated HBV Substitutions

In controlled clinical trials, YMDD-mutant HBV was detected in subjects with on-Epivir-HBV^® re-appearance of HBV DNA after an initial decline below the assay limit.18 Adult and pediatric subjects treated with Epivir-HBV^® with YMDD-mutant HBV at 52 weeks showed decreased treatment responses in comparison with those treated with Epivir-HBV^® without evidence of YMDD substitutions, including the following: lower rates of HBeAg seroconversion and HBeAg loss (no greater than placebo recipients), more frequent return of positive HBV DNA, and more frequent ALT elevations.18 In the controlled trials, when subjects developed YMDD-mutant HBV, they had a rise in HBV DNA and ALT from their previous on-treatment levels.18 Progression of hepatitis B, including death, has been reported in some subjects with YMDD-mutant HBV, including patients in a liver transplant setting and from other clinical trials.18 To decrease the risk of resistance in patients receiving Epivir-HBV^® alone, switching to an alternative regimen should be considered if serum HBV DNA remains detectable after 24 weeks of therapy.18 Optimal treatment should be guided by resistance testing.18

Specific Populations

Pregnancy

Lamivudine crosses the placenta and is distributed into cord blood in concentrations similar to maternal serum concentrations.1,18

To monitor maternal-fetal outcomes of pregnant women exposed to antiretroviral agents, including lamivudine, the Antiretroviral Pregnancy Registry was established.1,18 Clinicians are encouraged to contact the registry at 800-258-4263 or [Web] to report cases of prenatal exposure to antiretroviral agents.1,18

Data from the Antiretroviral Pregnancy Registry show no difference in the risk of overall major birth defects for lamivudine compared with the background rate for major birth defects in the US reference population of the Metropolitan Atlanta Congenital Defects Program (MACDP).1,18 Reproduction studies in rats or rabbits using oral lamivudine dosages that resulted in plasma concentrations up to approximately 35 times higher than plasma concentrations attained with the recommended human dosage used for the treatment of HIV infection in adults have not revealed evidence of teratogenicity.1 Although there was evidence of early embryolethality in rabbits at exposure levels similar to those observed in humans, this effect was not seen in rats at exposure levels up to 35 times higher than those in humans.1,18

Lactation

Lamivudine is distributed into milk in humans.1,18,202 It is not known whether the drug affects human milk production or affects the breast-fed infant.1,18

Because of the risk of transmission of HIV to an uninfected infant through breast milk, the HHS Panel and the US Centers for Disease Control and Prevention (CDC) recommend that HIV-infected women not breast-feed infants, regardless of antiretroviral therapy.1,202 Therefore, because of the potential for HIV transmission and the potential for serious adverse effects from lamivudine in nursing infants, women should be instructed not to breast-feed while they are receiving lamivudine.1

If lamivudine is being used for treatment of chronic HBV infection, the benefits of breast-feeding and the importance of lamivudine to the woman should be considered along with the potential adverse effects on the breast-fed infant from the drug or from the underlying maternal condition.18

Females and Males of Reproductive Potential

In animal studies involving lamivudine administration producing plasma levels 47-104 times those in humans, no evidence of impaired fertility and no effect on survival, growth, and development to weaning of the offspring were detected.1,18

Pediatric Use

The safety and efficacy of lamivudine for HIV-1 (Epivir^®) have been established in pediatric patients 3 months of age and older.1 The scored tablet is the preferred formulation for HIV-1-infected pediatric patients weighing at least 14 kg for whom a solid dosage form is appropriate; in the ARROW trial, pediatric patients who received the oral solution had lower rates of virologic suppression, lower plasma lamivudine exposure, and developed viral resistance more frequently.1

The safety and efficacy of lamivudine for chronic HBV (Epivir-HBV^®) in pediatric patients younger than 2 years have not been established.18

Geriatric Use

Clinical trials of lamivudine (Epivir^® and Epivir-HBV^®) did not include sufficient numbers of subjects 65 years of age or older to determine whether they respond differently from younger subjects.1,18 Use caution when administering lamivudine to elderly patients, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.1,18

Hepatic Impairment

Pharmacokinetic parameters of lamivudine were not altered by diminishing hepatic function.1,18 Safety and efficacy of lamivudine have not been established in the presence of decompensated liver disease.1,18

Renal Impairment

The dosage of lamivudine should be reduced in patients with renal impairment (see Tables 3 and 4).1,18 Time to maximum concentration is not significantly affected by renal function.1,18 In a trial including otherwise healthy subjects with impaired renal function, hemodialysis increased lamivudine clearance; however, the length of time of hemodialysis (4 hours) was insufficient to significantly alter mean lamivudine exposure after a single-dose administration.1,18 Continuous ambulatory peritoneal dialysis and automated peritoneal dialysis have negligible effects on lamivudine clearance.1,18 Therefore, it is recommended, following correction of dose for creatinine clearance, that no additional dose modification be made after routine hemodialysis or peritoneal dialysis.1,18 The effects of renal impairment on lamivudine pharmacokinetics in pediatric patients are not known.1,18

Common Adverse Effects

In the treatment of HIV infection in adults, the most common reported adverse reactions (incidence ≥15%) were headache, nausea, malaise and fatigue, nasal signs and symptoms, diarrhea, and cough.1 In the treatment of HIV infection in pediatric patients, the most common reported adverse reactions (incidence ≥15%) were fever and cough.1

In the treatment of HBV infection, the most common reported adverse reactions (incidence ≥10% and reported at a rate greater than placebo) were ear, nose, and throat infections; sore throat; and diarrhea.18

The following drug interactions are based on studies using lamivudine.1 Additional drug interactions may exist for fixed-dose combination products containing lamivudine/zidovudine (Combivir^®, generic)227 , abacavir/lamivudine (Epzicom^®, generic)228 , abacavir/lamivudine/zidovudine (Trizivir^®, generic)229 , lamivudine/tenofovir disoproxil fumarate (Cimduo^®)310 , doravirine/lamivudine/tenofovir disoproxil fumarate (Delstrigo^®)311 , dolutegravir/lamivudine (Dovato^®)312 , efavirenz/lamivudine/tenofovir disoproxil fumarate (Symfi^®; Symfi^® Lo)313,314 , and abacavir/dolutegravir/lamivudine (Triumeq^®; Triumeq PD^®).240 See the full prescribing information for information on each of these combination products.227,228,229,240,310,311,312,313,314

Drugs Affecting or Affected by Membrane Transporters

Based on in vitro studies, lamivudine at clinically important concentrations is not expected to affect the pharmacokinetics of drugs that are substrates of organic anion transporter polypeptide 1B1/3 (OATP1B1/3), breast cancer resistance protein (BCRP), P-glycoprotein (P-gp), multidrug and toxin extrusion protein (MATE) 1 or MATE2-K, organic cation transporter (OCT) 1, OCT2, or OCT3.1,18

Lamivudine is predominantly eliminated in the urine by active organic cationic secretion.1,18 Consider the possibility of interactions with other drugs administered concurrently, particularly when their main route of elimination is active renal secretion via the OCT system (e.g., trimethoprim).1,18 No data are available regarding interactions with other drugs that have renal clearance mechanisms similar to that of lamivudine.1,18

Lamivudine is a substrate of P-gp and BCRP; however, it is unlikely that these transporters play a clinically important role in the absorption of lamivudine.1,18 Therefore, concomitant use of drugs that are inhibitors of these efflux transporters is unlikely to affect the disposition and elimination of lamivudine.1,18

Lamivudine is a substrate of MATE1, MATE2-K, and OCT2 in vitro.1,18

Interferon Alfa and Peginterferon Alfa

Concomitant use of interferon alfa and lamivudine does not result in clinically important pharmacokinetic interactions.1,18

Ribavirin

Concomitant use of ribavirin and lamivudine does not result in clinically important pharmacokinetic interactions.1,18

Sorbitol

Concomitant use of sorbitol and lamivudine results in a sorbitol dose-dependent decrease in lamivudine exposures.1,18 When healthy adults received a single 300-mg dose of lamivudine oral solution alone or in conjunction with a single 3.2-, 10.2-, or 13.4-g dose of sorbitol in solution, peak plasma concentrations of lamivudine were decreased 28, 52, or 55%, respectively, and the AUC of lamivudine was decreased 20, 39, or 44%, respectively.1,18

Concomitant use of lamivudine and sorbitol-containing preparations should be avoided whenever possible.1,18 If chronic concomitant use of sorbitol cannot be avoided in patients receiving lamivudine for the treatment of chronic HBV infection, more frequent monitoring of HBV viral load should be considered.18

Trimethoprim

Trimethoprim has been shown to increase lamivudine plasma concentrations.1,18 However, this interaction is not considered clinically important and lamivudine dosage adjustments are not needed.1,18

Description

Lamivudine, an antiretroviral agent, is a human immunodeficiency virus (HIV) nucleoside reverse transcriptase inhibitor (NRTI).1,4,9 Following conversion to a pharmacologically active metabolite, lamivudine apparently inhibits replication of human retroviruses by interfering with viral RNA-directed DNA polymerase (reverse transcriptase).1 Lamivudine, therefore, exerts a virustatic effect against retroviruses by acting as a reverse transcriptase inhibitor.1,7

Like other HIV nucleoside reverse transcriptase agents and other nucleoside antiviral agents, the antiviral activity of lamivudine appears to depend on intracellular conversion of the drug to a 5'-triphosphate metabolite; thus, 2',3'-dideoxy,3'-thiacytidine-5'-triphosphate (3TC-TP) and not unchanged lamivudine appears to be the pharmacologically active form of the drug.1 3TC-TP is a structural analog of deoxycytidine triphosphate (dC-TP), the natural substrate for reverse transcriptase (viral RNA-directed DNA polymerase).1 Although other mechanisms may be involved in the antiretroviral activity of the drug, 3TC-TP appears to compete with naturally occurring dC-TP for incorporation into viral DNA by reverse transcriptase.7 Following incorporation of 3TC-TP into the viral DNA chain instead of dC-TP, viral DNA synthesis is terminated prematurely because the absence of a 3'-hydroxy group on the oxathiolane ring prevents further 5' to 3' phosphodiester linkages.7

Lamivudine is rapidly absorbed from the GI tract in patients with HIV or hepatitis B virus (HBV) infection.1,18 In HIV-infected patients or healthy individuals, peak plasma concentrations are achieved within 0.5-2 hours after a single dose.18 The absolute bioavailability of lamivudine 150-mg scored tablets and oral solution in adults is similar (86 and 87%, respectively).1 In a crossover study in healthy adults evaluating the steady-state pharmacokinetics of lamivudine administered in a once-daily regimen (300-mg tablet once daily) or twice-daily regimen (150-mg tablet twice daily), AUC was similar with both regimens; however, peak plasma concentrations were 66% higher and trough concentrations were 53% lower with the once-daily regimen compared with the twice-daily regimen.1

The absolute bioavailability of lamivudine tablets and lamivudine oral solution is lower in children than in adults.1 In addition, the relative bioavailability of the oral solution is approximately 40% lower than that of the tablets in children, despite no difference between the preparations in adults.1 It has been suggested that lower lamivudine exposures reported in pediatric patients receiving lamivudine oral solution are likely due to an interaction between lamivudine and concomitant solutions containing sorbitol (e.g., abacavir oral solution).1 Data from pharmacokinetic studies evaluating once- and twice-daily lamivudine regimens in HIV-1-infected pediatric patients 3 months through 12 years of age indicate that AUCs attained with once-daily regimens were similar to those attained with twice-daily regimens when comparing the dosage regimens within the same formulation (i.e., either tablets or the oral solution).1 However, mean peak plasma concentrations were approximately 80-90% higher with once-daily lamivudine regimens compared with twice-daily lamivudine regimens.1

Pharmacokinetics of lamivudine in pregnant women are similar to those reported in nonpregnant adults and postpartum women.1,202 Food does not appear to affect the AUC of lamivudine.1,18 In a small study in HIV-infected patients, peak plasma concentrations of lamivudine were decreased 40% and the rate of absorption was reduced when lamivudine was administered with food, but clinically important decreases in systemic availability of the drug (AUC) were not observed.1

Lamivudine is distributed into CSF.1 In HIV-infected children who received oral lamivudine in a dosage of 8 mg/kg daily, CSF concentrations ranged from 0.04-0.3 mcg/mL and were 5.6-30.9% of concurrent serum concentrations.1 Lamivudine crosses the placenta and is distributed into cord blood and amniotic fluid.1,18 Lamivudine concentrations in amniotic fluid are typically twofold higher than maternal serum concentrations and have ranged from 1.2-2.5 mcg/mL or 2.1-5.2 mcg/mL when lamivudine dosage in the mother was 150 or 300 mg twice daily, respectively.1 Lamivudine is distributed into milk.1,18 Lamivudine is less than 36% bound to plasma proteins.1,18

Intracellularly, lamivudine is phosphorylated and converted by cellular enzymes to the active 5'-triphosphate metabolite.1,18 Lamivudine is not substantially metabolized by cytochrome P-450 (CYP) isoenzymes.1 Metabolism is a minor route of elimination of lamivudine; the only known metabolite is the trans-sulfoxide metabolite.1,18 The majority of a lamivudine dose is eliminated unchanged in urine by active organic cationic secretion.1,18 Within 12 hours after an oral dose, approximately 5% is excreted in urine as the trans-sulfoxide metabolite.1 In single-dose studies in healthy individuals or patients with HIV or HBV infection, the mean plasma half-life of lamivudine was 5-7 hours.1,18 The plasma half-life in HIV-infected children 4 months to 14 years of age is 2 hours.1

The pharmacokinetics of lamivudine are not altered in patients with hepatic impairment.1,18 In patients with impaired renal function, peak plasma concentrations, AUC, and plasma half-life of lamivudine are increased.1,18 Hemodialysis increases lamivudine clearance; however, the length of time of hemodialysis (4 hours) is insufficient to substantially alter mean lamivudine exposure after a single dose of the drug.1,18 Continuous ambulatory peritoneal dialysis and automated peritoneal dialysis have negligible effects on lamivudine clearance.1,18 There are no significant or clinically relevant racial or gender differences in lamivudine pharmacokinetics.1,18

Spectrum

Lamivudine is an antiviral agent that possesses in vitro virustatic activity against HIV-11,2,3,10 and HIV-2.10 The drug is also active against human HBV12,24,26,59 but appears to be inactive against other common human viruses (e.g., cytomegalovirus, Epstein-Barr virus, influenza virus, herpes simplex virus types 1 and 2, respiratory syncytial virus, varicella-zoster virus).10

Resistance

Resistance to lamivudine can be produced in vitro in cell culture by serial passage of HIV-1 in the presence of increasing concentrations of the drug,1,10 and strains of HIV-1 with in vitro resistance to lamivudine have emerged during therapy with the drug.1,10,31

Cross-resistance occurs among the HIV NRTIs.1 HIV isolates resistant to didanosine, lamivudine, stavudine, and zidovudine have been isolated from patients who received zidovudine in conjunction with didanosine for up to 2 years.44

Evidence of diminished treatment response has been reported in adult and pediatric patients with HBV infection following 52 weeks of lamivudine therapy.18 Lamivudine-resistant HBV develops M204V/I substitutions in the YMDD motif of the catalytic domain of HBV reverse transcriptase.18 These substitutions are frequently accompanied by other substitutions (V173L, L180M) that enhance lamivudine resistance or act as compensatory mutations improving replication efficiency.18 L80I and A181T substitutions also have been detected in lamivudine-resistant HBV.18

In controlled clinical trials, YMDD-mutant HBV were detected in 19% of pediatric patients and in 24% (range: 16-32%) of adults who received lamivudine for 52 weeks.18 In follow-up studies of patients who continued to receive lamivudine therapy, the prevalence of YMDD mutations in pediatric patients increased from 24% at 12 months to 59% at 24 months and 64% at 36 months of lamivudine treatment.18 Similarly, in a follow-up study in adults, the prevalence of YMDD mutations was 18% at 1 year and 41, 53, and 69% at 2, 3, and 4 years, respectively.18

Some lamivudine-resistant HBV remain susceptible to adefovir dipivoxil but have reduced susceptibility to entecavir and telbivudine.18 Other lamivudine-resistant HBV have reduced susceptibility to telbivudine and/or tenofovir.18

Advice to Patients

• When used for treatment of chronic HBV infection, advise patients that the long-term benefits of the drug are unknown and that the relationship between treatment response and outcomes, such as hepatocellular carcinoma and decompensated cirrhosis, is also unknown.18 Explain importance of reporting any new symptoms to a clinician.18
• Advise patients that lactic acidosis and severe hepatomegaly with steatosis have been reported with use of nucleoside analogs and other antiretrovirals.1,18 Explain importance of discontinuing lamivudine and notifying a clinician if symptoms suggestive of lactic acidosis or pronounced hepatotoxicity develop.1,18
• Advise patients that an all-tablet regimen should be used when possible due to an increased rate of treatment failure among pediatric subjects who received lamivudine (Epivir^®) oral solution concomitantly with other antiretroviral oral solutions.1
• Advise diabetic patients receiving lamivudine oral solutions that each mL contains 200 mg of sucrose.1,18
• Advise patients to immediately contact a clinician if they have any signs or symptoms of infection since inflammation from previous infections may occur soon after antiretroviral therapy is initiated.1
• Explain that redistribution/accumulation of body fat may occur, with as yet unknown long-term health effects.1
• Explain the possibility for pancreatitis in pediatric patients; advise parents or guardians to monitor pediatric patients for signs and symptoms.1
• Advise patients to inform their clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1,18
• Advise women to inform their clinician if they are or plan to become pregnant or plan to breast-feed.1,18 Instruct HIV-infected women not to breast-feed due to risk of HIV transmission and adverse effects in the infant.4
• Advise patients of other important precautionary information.1,18

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

1. ViiV Healthcare. Epivir^® (lamivudine) tablet, film coated and solution prescribing information. Research Triangle Park, NC; 2020 Sep.

2. Soudeyns H, Yao XJ, Gao Q et al. Anti-human immunodeficiency virus type 1 activity and in vitro toxicity of 2'-deoxy-3'-thiacytidine (BCH-189), a novel heterocyclic nucleoside analog. Antimicrob Agents Chemother . 1991; 35:1386-90. [PubMed 1929298]

3. Coates JAV, Cammack N, Jenkinson HJ et al. The separated enantiomers of 2'-deoxy-3'-thiacytidine (BCH 189) both inhibit human immunodeficiency virus replication in vitro. Antimicrob Agents Chemother . 1992; 36:202-5. [PubMed 1590690]

4. Pluda JM, Cooley TP, Montaner JSG et al. A phase I/II study of 2'-deoxy-3'-thiacytidine (lamivudine) in patients with advanced immunodeficiency virus infection. J Infect Dis . 1995; 171:1438-47. [PubMed 7769277]

6. Eron JJ, Benoit SL, Jemsek J et al. Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter. N Engl J Med . 1995; 333:1662-9. [PubMed 7477218]

7. Hayden FG. Antiviral Agents. In: Hardman JG, Limbird LE, Molinoff PB et al eds. Goodman and Gilman's the pharmacological basis of therapeutics. 9th ed. New York: McGraw -Hill; 1996:1191-1223.

9. van Leeuwen R, Katlama C, Kitchen V et al. Evaluation of safety and efficacy of 3TC (lamivudine) in patients with asymptomatic or mildly symptomatic human immunodeficiency virus infection: a phase I/II study. J Infect Dis . 1995; 171:1166-71. [PubMed 7751691]

10. Coates JAV, Cammack N, Jenkinson HJ et al (-)-2'-deoxy-3'-thiacytidine is a potent, highly selective inhibitor of human immunodeficiency virus type 1 and type 2 replication in vitro. Antimicrob Agents Chemother . 1992; 36:733-9.

11. Doong SL, Tsai CH, Schinazi RF et al. Inhibition of the replication of hepatitis B virus in vitro by 2',3'-dideoxy-3'-thiacytidine and related analogues. Proc Natl Acad Sci USA . 1991; 88:8495-9. [PubMed 1656445]

12. Benhamou Y, Dohin E, Lunel-Fabiani F et al. Efficacy of lamivudine on replication of hepatitis B virus in HIV-infected patients. Lancet . 1995; 345:396-7. [PubMed 7845151]

13. van Leeuwen R, Lange JMA, Hussey EK et al The safety and pharmacokinetics of a reverse transcriptase inhibitor, 3TC, in patients with HIV infection: a phase I study. AIDS . 1992; 6:1471-5.

14. Merrill DP, Moonis M, Chou TC et al. Lamivudine or stavudine in two- and three-drug combinations against human immunodeficiency virus type 1 replication in vitro. J Infect Dis . 1996; 173:355-64. [PubMed 8568296]

18. GlaxoSmithKline. Epivir-HBV^® (lamivudine) tablets, film-coated and oral solution prescribing information. Research Triangle Park, NC; 2021 Dec.

24. Dienstag JL, Perrillo RP, Schiff ER et al A preliminary trial of lamivudine for chronic hepatitis B infection. N Engl J Med . 1995; 333:1657-61.

26. Merigan TC. A quarter-century of antiviral therapy. N Engl J Med . 1995; 333:1704-5. [PubMed 7477225]

29. Katlama C, Ingrand D, Loveday C et al. Safety and efficacy of lamivudine-zidovudine combination therapy in antiretroviral-naive patients. JAMA . 1996; 276:118-25. [PubMed 8656503]

30. Staszewski S, Loveday D, Picazo JJ et al. Safety and efficacy of lamivudine-zidovudine combination therapy in zidovudine-experienced patients. JAMA . 1996; 276:111-17. [PubMed 8656502]

31. Puoti M, Airoldi M, Bruno R et al. Hepatitis B virus co-infection in human immunodeficiency virus-infected subjects. AIDS Rev . 2002; 4:27-35. [PubMed 11998781]

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