1. Introduction

2. Overview of the market

3. Introduction to the compound

4. Pharmacodynamics

5. Pharmacokinetics and

metabolism

6. Clinical efficacy

7. Safety and tolerability and

regulatory affairs

8. Expert opinion

Drug Evaluation

Lamivudine for the treatmentof HIVPrincy N Kumar† & Parul Patel†Georgetown University, 110 Kober Cogan Building, 3800 Reservoir Rd NW,

Washington DC, 20007, USA

Lamivudine is a nucleoside reverse transcriptase inhibitor that is widely used

for the treatment of HIV-1 infection in combination with other antiretrovirals.

It is a highly effective agent that can be dosed once or twice daily due to its

long intracellular half-life. It also has one of the best tolerability and long-term

safety profiles among all antiretroviral agents and continues to be preferred as

part of initial or subsequent combination therapy in HIV-infected patients.

Keywords: antiretroviral therapy, HIV, lamivudine, nucleoside reverse transcriptase inhibitor

Expert Opin. Drug Metab. Toxicol. (2010) 6(1):105-114

1. Introduction

It is estimated that 40 million individuals are infected with the HIV-1 virusworldwide of which ~ 1 million are in the US. Antiretroviral agents have beenavailable in developed countries since the beginning of the epidemic and over thelast decade, generic versions of these drugs have become increasingly available indeveloping countries. At the outset of this epidemic in western developedcountries, HIV infection appeared limited to young, white, homosexual males;however, an increasing proportion of cases are being diagnosed in women,adolescents, African-American, Hispanic and older individuals. The incidenceof HIV infection in Africa and other developing countries has not substantiallydecreased despite the availability of antiretroviral therapy (ART). In industrializednations, the advent of highly active antiretroviral therapy (HAART) has substan-tially reduced the morbidity and mortality of HIV infection and transformed itinto a chronic, manageable condition. Thus, the focus has shifted to understandingthe implications of aging with HIV including the development of co-morbidconditions such as cardiovascular disease, diabetes, renal disease and cognitivedecline. Moreover, it is important to investigate the potential differences in theprogression and management of HIV and co-morbid conditions in newly diag-nosed individuals who are > 50 years of age. Despite its beneficial effect on survival,HAART has a number of risks including short- and long-term toxicities. Theseinclude insulin resistance, hyperlipidemia and fat redistribution, which may alsocontribute to the development of cardiovascular disease. Early HAART regimenswere associated with multiple daily doses, high pill burdens particularly fromprotease inhibitor agents, food restrictions, numerous drug interactions and mild-to-severe gastrointestinal toxicity that may have impacted adherence patternscompared to contemporary regimens boasting once-daily convenience, improvedtolerability, favorable long-term safety profiles, reduced drug–drug interactionpotential and activity against resistant viruses. Initial nucleoside reverse transcrip-tase inhibitors (NRTIs) approved during the late 1980s and early 1990s wereplagued with toxicities such as anemia, lactic acidosis, pancreatitis, hepatotoxicity,mitochondrial toxicity and peripheral neuropathies and although still used are nowrelegated mostly for use in later line or salvage situations. Lamivudine was the firstNRTI with an improved tolerability and safety profile and because of these factorsas well as a psitive synergistic effect on zidovudine-resistant virus, it remains a

10.1517/17425250903490418 © 2010 Informa UK Ltd ISSN 1742-5255 105All rights reserved: reproduction in whole or in part not permitted

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mainstay of combination HAART. It can be administeredonce or twice daily and has been co-formulated inthree separate fixed dose combination (FDC) tablets. Ithas been used in combination to prevent mother-to-child transmission of HIV, in post-exposure prophylaxisregimens and as monotherapy for the treatment ofhepatitis B infection.Lamivudine (3TC) (Box 1) was the fifth NRTI approved

by the US FDA for the treatment of HIV infection in 1995and was the first agent approved for the treatment ofhepatitis B virus (HBV) in 1998 (Table 1). As a class,NRTIs are less potent than protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). However,HAART regimens typically consist of two nucleoside agents,

an NNRTI or a PI in combination to achieve maximal viralload reduction than either agent achieves alone.

Slight regional variations in treatment guidelines exist;however, the US Department of Health and Human Services(DHHS), the International AIDS Society (IAS) and theWorld Health Organization (WHO), all currently recom-mend initial use of lamivudine as part of combination therapyin antiretroviral naı̈ve patients [1,2,3].

2. Overview of the market

Six antiretroviral classes consisting of 24 individual agents arecurrently FDA-approved: these include 8 NRTIs, 4 NNRTIs,9 PIs, 1 integrase inhibitor, 1 chemokine co-receptor 5 (CCR5)

Box 1. Drug summary.

Drug name Lamivudine

Phase Launched

Indication Infection, HIV/AIDSInfection, hepatitis B virus

Pharmacologydescription

RNA directed DNA polymerase inhibitorNucleoside reverse transcriptase inhibitor

Route ofadministration

Alimentary, by mouth

Chemicalstructure

N

N

N

O

O

S

O

Pivotal trial(s) HIV/AIDSNUCB3007 (CAESAR): multicenter, randomized, double-blind, placebo-controlled trial of 1,816 HIV-1 infectedadults that compared 3TC versus 3TC + investigational NNRTI versus placebo each with concurrent ZDV-basedtherapy (ZDV alone, ZDV + ddI or ZDV + ddC).EPV20001: multicenter, randomized, double-blind trial of 554 antiretroviral treatment-naive HIV-1 infectedadults that compared 3TC once daily versus 3TC twice daily each with ZDV + EFV. Hepatitis BFour controlled studies in 967 patients with compensated chronic hepatitis B were conducted. Three studiesprovided comparisons of EPIVIR-HBV 100 mg q.d. versus placebo as briefly summarized below.Study 1: randomized, double-blind study of EPIVIR-HBV once daily versus placebo for 52 weeks followed by a16-week no-treatment period in treatment-naive US patients.Study 2: randomized, double-blind, three-arm study that compared EPIVIR-HBV 25 mg q.d. versus EPIVIR-HBV100 mg q.d. versus placebo for 52 weeks in Asian patients.Study 3: randomized, partially blind, three-arm study in North America and Europe in patients who had ongoingevidence of active chronic hepatitis B despite previous treatment with IFN-a. The study compared EPIVIR-HBVonce daily for 52 weeks, followed by either EPIVIR-HBV or matching placebo once daily for 16 weeks (arm 1),versus placebo once daily for 68 weeks (arm 2). (A third arm using a combination of IFN and lamivudine was notpresented because of insufficient information to evaluate this regimen.)

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Lamivudine

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antagonist and 1 fusion inhibitor (Table 2). New antiretroviralagents currently in development include NRTIs (amdoxovir,apricitabine, GS-9148), NNRTIs (TMC-278, IDX899,RDEA806, UK-453061), PIs (SPI-256), integrase inhibitors(elvitegravir, S/GSK1349572), CCR5 antagonists (vicriviroc,SCH417690), fusion inhibitors (BMS-488043), entry inhi-bitors (TNX-355, PRO140), pharmacokinetic enhancers(GS-9350, SPI-452, PF-3716539), a maturation inhibitor(bevirimat) and novel gene-based therapies.

3. Introduction to the compound

Lamivudine is a cytosine nucleoside analogue and acompetitive inhibitor of the HIV-1 and HBV reverse tran-scriptase enzymes. It is the negative enantiomer of 2¢,3¢-dideoxy-3¢-thiacytidine, a dideoxypyridimine, in which the3¢ carbon of the ribose ring is replaced by a sulfur atom [4].This substitution allows lamivudine to be resistant to cleavagefrom the 3¢ terminals of the RNA/DNA complexesby 13¢,5¢-exonuclease [5]. Lamivudine antiviral acti-vity is dependent on intracellular phosphorylation to itsactive 5¢-triphosphate metabolite (3TC-TP), which when

incorporated into the growing DNA chain results in prematurechain termination [6].

4. Pharmacodynamics

Lamivudine is preferentially activated in resting peripheralblood mononucleocytes (PBMCs) in both infected and non-infected cells. It is a poor substrate for nuclear and mitochon-drial human DNA polymerase a, b and g and has a favorablesafety profile as evident in clinical trials compared to othernucleoside analogues [7-11]. In vitro, the IC90 of lamivudineagainst HIV-1 in various cell lines ranged from 8.7 to 464 µg/l(0.03 – 1.6 µmol/l) and the IC50 against HBV in hepatic celllines ranged from 4 to 7 µg/l (0.018 – 0.032 µmol/l) [12].

Lamivudine monotherapy is associated with an initialHIV-1 RNA reduction of 1.3 logs over 2 – 4 weeks followedby a rebound in viral load due to the rapid selection of theM184V mutation that results in an overall viral load reduc-tion by 0.5 logs over 48 weeks. This has been observed inboth antiretroviral-naı̈ve and treatment-experienced patientsincluding individuals with high-level phenotypic resistance tolamivudine and thymidine analogues [8,13-15]. The initial1.3 log viral load drop with lamivudine is similar to thatobserved with tenofovir DF with a 1.5 log10 decrease in HIV-1RNA over 21 days in treatment-naive patients [8,16,17]. Theoverall reduction in viral load is similar to that observed withabacavir sulfate (0.7 log10 decrease) and zidovudine (0.3 log10decrease), both administered separately through 24 weeks oftherapy [8,16]. The subsequent viral rebound that occurs afteran initial 1.3 log drop results from rapid development ofresistance with lamivudine monotherapy. A methionine tovaline substitution at codon 184 (M184V mutation) in theHIV-1 reverse transcriptase coding region is responsible forresistance to lamivudine. However, acquisition of theM184V mutation is associated with a beneficial delay inthe emergence of zidovudine-resistant mutants in zidovu-dine-naı̈ve patients, restoration of zidovudine sensitivity insome patients already possessing zidovudine associated resis-tance mutations and impairment of HIV-1 replication capac-ity and virulence [12], resulting in continued benefit even forthose patients infected with lamivudine-resistant HIV-1. Forthe treatment of HIV, lamivudine can be taken either as a300 mg q.d. tablet or as a 150 mg tablet b.i.d. in combi-nation with other antiretrovirals. However, lamivudine hasbeen co-formulated with other NRTIs in convenient FDCtablets (Table 3). It takes advantage of synergistic antiviralactivity with zidovudine and is administered twice daily.Lamivudine has also been co-formulated with abacavir sul-fate, which is administered once daily and co-formulatedwith both zidovudine and abacavir sulfate into a triple NRTIFDC tablet administered twice daily. For hepatitis B treat-ment, lamivudine is administered at a dosage of 100 mg q.d.;for HIV-HBV co-infected patients, lamivudine is adminis-tered at the higher HIV treatment dosage of 300 mg/day.Clinical trial data of HIV treatment regimens containing

Table 1. Lamivudine dosing recommendations.

A. In adult and pediatric populations.

Adult andadolescents> 16 years of age

Pediatric

300 mg q.d. or150 mg b.i.d.

3 months to 16 years: 4 mg/kg b.i.d. p.o.in solution* form (up to maximum of150 mg b.i.d.)

‡ 14 kg for whom solid dosage form isappropriate:

Weight range Scored 150 mg tabletdosing

14 – 21 kg ½ tablet (75 mg) b.i.d.

> 21 to < 30 kg ½ tablet (75 mg) a.m.+ 1 tablet (150 mg) p.m.

‡ 30 kg 1 tablet (150 mg) b.i.d.

B. In adults and adolescents (‡ 30 kg) with impaired renalfunction.

Creatinineclearance (ml/min)

Recommended dosage of lamivudine‡

‡ 50 150 mg b.i.d. or 300 mg q.d.

30 – 49 150 mg q.d.

15 – 29 150 mg first dose, then 100 mg q.d.

5 – 14 150 mg first dose, then 50 mg q.d.

< 5 50 mg first dose, then 25 mg q.d.

*Lamivudine is also available in a 10 mg/ml liquid formulation for

administration to pediatric patients 3 months to 16 years of age.‡There is insufficient data to recommend specific dose adjustments in

pediatric patients with renal impairment; however, a reduction in the dose

and/or increase in the dosing interval should be considered.

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lamivudine in combination with zidovudine or abacavir,administered as separate components or as FDC tabletswith a variety of third agents, have resulted in sustainedelevations in mean CD4+ count and reduction of HIV-1RNA to below the limits of detectability [either < 400 copies/ml (c/ml) or <50 c/ml] through 144 weeks [8-11,18-31]. Addi-tionally, lamivudine is one of the few antiretrovirals that hasdemonstrated survival benefit for HIV-1 infectedpatients [18,32].

In the treatment of chronic HBV infection, lamivudinemonotherapy has significantly reduced HBV DNA levels,reduced hepatic necroinflammatory activity, normalizedaminotransferases levels and improved liver fibrosis [33-40].

5. Pharmacokinetics and metabolism

The pharmacokinetics of lamivudine has been studied in avariety of patient populations. Lamivudine is highly soluble

Table 2. Currently available antiretroviral agents.

Class Generic name Brand name and

abbreviation

Manufacturer FDA approval

date

Nucleoside reversetranscriptase inhibitors

Zidovudine Retrovir, ZDV, AZT GlaxoSmithKline 1987

Stavudine Zerit, d4T Bristol-Myers Squibb 1994

Lamivudine Epivir, 3TC GlaxoSmithKline 1995

Didanosine Videx, Videx EC, ddI Bristol-Myers Squibb 1991, 2000 (EC)

Abacavir Ziagen, ABC GlaxoSmithKline 1998

Tenofovir DF Viread, TDF Gilead Sciences 2001

Emtricitabine Emtriva, FTC Gilead Sciences 2003

Non-nucleoside reversetranscriptase inhibitors

Delavirdine Rescriptor, DLV Pfizer 1997

Efavirenz Sustiva, EFV Bristol-Myers Squibb 1998

Nevirapine Viramune, NVP Boehringer Ingelheim 1996

Etravirine Intelence, TMC125, ETR Tibotec 2008

Protease inhibitors Saquinavir Invirase, SQV Hoffman-La Roche 1995

Ritonavir Norvir, RTV Abbott Laboratories 1996

Indinavir Crixivan, IDV Merck 1996

Nelfinavir Viracept, NFV AgouronPharmaceuticals/Pfizer

1997

Amprenavir Agenerase, APV GlaxoSmithKline,Vertex Pharmaceuticals

1999

Lopinavir/ritonavir Kaletra, LPV/r Abbott Laboratories 2000

Atazanavir Reyataz, ATV Bristol-Myers Squibb 2003

Fosamprenavir Lexiva, FPV GlaxoSmithKline,Vertex Pharmaceuticals

2003

Tipranavir Aptivus, TPV Boehringer Ingelheim 2005

Darunavir Prezista, TMC114, DRV Tibotec 2006

Entry/fusion inhibitors Enfuvirtide Fuzeon, T-20 Hoffman-La Roche,Trimeris

2003

Maraviroc Selzentry, MVC Pfizer 2007

Integrase inhibitors Raltegravir Isentress, RAL Merck 2007

Fixed dose combinationproducts

Lamivudine,Zidovudine

Combivir, 3TC/ZDV, CBV GlaxoSmithKline 1997

Abacavir sulfate,Lamivudine,Zidovudine

Trizivir, ABC/3TC/ZDV, TZV GlaxoSmithKline 2000

Abacavir sulfate,Lamivudine

Epzicom, ABC/3TC, EPZ GlaxoSmithKline 2004

Emtricitabine,Tenofovir DF

Truvada, TDF/FTC, TRU Gilead Sciences 2004

Efavirenz, Emtricitabine,Tenofovir DF

Atripla, EFV/TDF/FTC Bristol-Myers Squibb,Gilead Sciences

2006

Lamivudine

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and permeable with a rapid dissolution rate. In HIV-1infected adults, lamivudine is rapidly absorbed via passivediffusion with an absolute bioavailability of 86% that is notimpacted by the presence of food. The maximum plasmaconcentration is achieved within 0.5 – 1.5 h following adose [12]. It is widely distributed with an apparent volumeof distribution of 1.3 l/kg indicating penetration into extra-vascular spaces [6]. Lamivudine is not highly protein bound(< 36%); it crosses the placenta and is excreted in breast milk.It is also present in cerebrospinal fluid and in the male andfemale genital tract [41-43]. Metabolism of lamivudine isminor with 5.2% of the dose excreted as the trans-sulfoxidemetabolite in the urine. The majority of lamivudine is elim-inated unchanged through the kidney via active organiccationic secretion. Dose adjustment is required in patientswith renal impairment [6]. The plasma half-life of lamivudineis 5 – 7 h; however, the active moiety, lamivudine triphos-phate, has an effective in vitro half-life of 10.5 – 15.5 h ininfected PBMCs, which provides the rationale for once dailyadministration [6,12,44].

Few drug interactions exist with lamivudine given itspH-independent solubility and lack of extensive metabolismor protein binding. Although no pharmacokinetic or phar-macodynamic interaction has been demonstrated whenlamivudine is coadministered with ribavirin in HCV- orHIV/HCV-infected patients, hepatic decompensation (somefatal) has occurred in HIV/HCV co-infected patients receivingcombination ART for HIV and interferon-a with or withoutribavirin [6]. No clinically significant interactions have beenobserved when lamivudine has been coadministered withzidovudine or trimethoprim/sulfamethoxazole [12].

The pharmacokinetics of lamivudine has also beenevaluated in the pediatric population. In children, the absol-ute bioavailability of lamivudine is reduced (range 59 – 76%)and apparent renal clearance is more rapid (CL/F

0.67 – 0.94 l/h/kg) when compared with adults [12,45,46].As a result, a twofold increase in lamivudine dose (4 mg/kgb.i.d., up to a maximum of 150 mg b.i.d.) is required inchildren 3 months to 16 years of age compared with adults(150 mg: ~ 2 mg/kg b.i.d.) [6,45]. In neonates administeredlamivudine during their first week of life, it is recommendedthat the dose be reduced to 2 mg/kg b.i.d. compared to4 mg/kg in older infants and children. The dosage differencesbetween neonates and older infants and children are likelycontributed by the presence of an immature renal system andaltered gastric pH in neonates [47].

Lamivudine has also been studied in adults with impairedrenal function since it is largely excreted unchanged in theurine. With diminishing renal function, lamivudine exposure(AUC¥) and half-life increase proportionally necessitating adose reduction [6,48]. Hemodialysis removes lamivudine effi-ciently with an extraction ratio approaching 50% increasinglamivudine clearance to a mean of 64 – 88 ml/min comparedwith a mean of 111 ml/min in otherwise healthy adults withcreatinine clearance > 60 ml/min. Following dose correctionfor creatinine clearance, no additional dose modification isrequired after routine hemodialysis or peritoneal dialysis [6,48].

6. Clinical efficacy

In contrast to hepatitis B treatment, lamivudine monotherapyis not recommended in treatment of HIV infection. Duringinitial development, lamivudine was compared as part of adual NRTI regimen of lamivudine plus zidovudine againstzidovudine monotherapy or zidovudine plus zalcitabine. Inmodern clinical trials, lamivudine is frequently used with oneor two NRTIs plus a third agent from another antiretroviralclass for improved viral suppression. Efficacy results from selectpivotal and/or contemporary trials containing lamivudineare reviewed.

6.1 Clinical trials in treatment-naive patientsThe NUC trials (NUCA 3001 in North America and NUCB3001 in Europe) evaluated lamivudine plus zidovudinecompared to zidovudine monotherapy. NUCA 3001 alsoevaluated lamivudine monotherapy. Subjects with < 4 weeksof previous zidovudine therapy were eligible to participate inboth studies, however, CD4+ cell count entry criteria differedslightly between studies. At 48 – 52 weeks, lamivudine pluszidovudine therapy resulted in CD4+ cell count increases of75 – 85 cells/mm3 that were sustained at 48 – 60 cells/mm3

above baseline. HIV-1 RNA levels were reduced from baselineby ~ 1 log10 with combination therapy. The combinationtreatment was superior to zidovudine monotherapy over thestudy periods using an average of the mean change frombaseline in CD4+ cell counts and HIV-1 RNA levels [49].

EPV20001 was a 48-week randomized, double-blind, mul-ticenter trial comparing lamivudine 300 mg q.d. or 150 mgb.i.d. each in combination with zidovudine 300 mg b.i.d. andefavirenz 600 mg q.d., in 554 treatment-naive HIV-1-infected

Table 3. Pharmaceutical formulations of lamivudine.

Trade name Dosage forms and strengths

Epivir� (GSK, Zebulon,NC, USA)

150 mg scored tablet300 mg tablet10 mg/ml oral solution

Epivir-HBV�*(GSK, Mississauga,Ontario, Canada)

100 mg tablet5 mg/ml oral solution

Combivir� (GSK, Zebulon,NC, USA)

150 mg lamivudine + 300 mgzidovudine scored FDC tablet

Trizivir� (GSK, Zebulon,NC, USA)

300 mg abacavir sulfate + 150 mglamivudine + 300 mg zidovudineFDC tablet

Epzicom�

(GSK, Ware, UK)300 mg abacavir sulfate + 150 mglamivudine FDC tablet

*Note the strength of Epivir-HBV� formulations is not equivalent to

corresponding Epivir� formulations.

FDC: Fixed dose combination; GSK: GlaxoSmithKline; HBV: Hepatitis B virus.

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adults [6,50]. Median baseline plasma HIV-1 RNA was4.66 log10 c/ml and 28% had baseline HIV-1 RNA> 100,000 c/ml. At 48 weeks, 64% of patients in the oncedaily arm versus 63% in the twice daily one achieved anHIV-1 RNA < 400 c/ml by an intent-to-treat, missing =failure analysis, with somewhat greater response rates in theonce daily arm among patients with baseline HIV-1 RNA> 100,000 c/ml (68 versus 53%). Viral suppression rates to< 50 c/ml were equivalent (59 versus 61%) between the onceand twice daily arms. Through week 48, mean CD4+ cellcount increases were 144 and 146 cells/mm3 in the once dailyand twice daily arms, respectively.GS-934 was a 144-week, multicenter, open-label trial

comparing co-formulated zidovudine/lamivudine versustenofovir DF plus emtricitabine each with efavirenz, in 509treatment-naive patients [26]. Mean baseline HIV-1 RNAwas 5.0 log10 c/ml and median CD4+ cell count was237 cells/mm3. At 144 weeks, 58% in the zidovudine/lamivudine arm compared to 71% in the tenofovir DFplus emtricitabine arm had an HIV-1 RNA < 400 c/ml usingthe FDA-mandated time to loss of viral response (TLOVR)analysis (p = 0.004). HIV-1 RNA suppression to < 50 c/mlwas reached by 56 and 64% of patients, respectively(p = 0.08). Lower success rate with the lamivudine-contain-ing regimen was driven by a higher discontinuation rateresulting from adverse events associated with zidovudine,such as anemia. There were no differences in CD4+ cellrecovery between arms.The AIDS Clinical Trials Group (ACTG) A5095 study was

a randomized, double-blind, placebo-controlled trial thatevaluated the efficacy and safety of three regimens: a triplenucleoside regimen (zidovudine/lamivudine/abacavir), astandard of care three-drug regimen (zidovudine/lamivudineplus efavirenz) or a four-drug regimen (zidovudine/lamivudine/abacavir plus efavirenz) for initial HIV treatmentin 1,147 patients. The mean baseline HIV-1 RNA was4.85 log10 c/ml and CD4+ cell count 238 cells/mm3. Aftera median of 32 weeks, the triple-nucleoside group was foundto have a significantly shorter time to virologic failure com-pared to the pooled efavirenz groups (p < 0.001) regardlessof pre-treatment viral load resulting in the premature dis-continuation of the triple nucleoside arm [51]. As a result,triple nucleoside therapy consisting of lamivudine/abacavir/zidovudine is now considered an alternative regimen for initialtherapy for patients in whom first-line regimens are notsuitable [1]. The remaining two arms were continued anddemonstrated no significant differences in efficacy between thethree-drug and four-drug regimens, each resulting in ~ 80%achieving an HIV-1 RNA < 50 c/ml through 3 years [27].Previous studies had demonstrated lamivudine-containing

triple nucleoside therapy to be as efficacious as regimenscontaining dual nucleosides with the PI indinavir or nelfinavir(NFV) [52-54]. Other triple nucleoside regimens that are notrecommended include tenofovir combined with lamivudine/abacavir sulfate (due to a high rate of virologic failure) and a

regimen of tenofovir, didanosine and lamivudine [55-58]. Withboth regimens, virologic failure was common in patients withbaseline viral loads > 100,000 c/ml and CD4+ cell counts< 200 cells/mm3.

Lamivudine has also been studied in combination withabacavir sulfate in several large clinical trials of therapy-naı̈vepatients. In CNA30021 and CNA30024, lamivudine com-bined with abacavir (given once or twice daily) and efavirenzresulted in 66 – 70% of patients reaching an HIV-1 RNA< 50 c/ml at week 48 in > 1,400 patients [59,60]. The KLEANstudy demonstrated that lamivudine/abacavir sulfate FDCwith either lopinavir/ritonavir or fosamprenavir/ritonavir(both PI) had comparable efficacy over 48 weeks andthrough the extension phase of 144 weeks [30,61]. Recently,the HEAT study demonstrated the non-inferiority oflamivudine/abacavir sulfate FDC compared to tenofovir/emtricitabine FDC each in combination with lopinavir/ritonavir over 96 weeks [31].

6.2 Clinical trials in treatment-experienced patientsLimited clinical data exist evaluating the effectiveness andsafety of lamivudine in combination with other antiretroviralsin treatment-experienced patients due to a greater degree oftreatment individualization required after failure of initialtherapy. Commonly, later lines of therapy are frequentlyconstructed on the basis of genotypic and phenotypic resis-tance test results as well as regimen convenience, tolerability,potency and safety. Efficacy results from trials that specifi-cally evaluated lamivudine in combination with otherantiretrovirals are reviewed.

CAL30001 was one of the first studies to evaluate thecombination of lamivudine and abacavir as part of a four-drugregimen in 186 treatment-experienced patients. At week 48,lamivudine with abacavir (once or twice daily) plus tenofovirplus either a new PI or an NNRTI resulted in 50 and 47% ofpatients with an HIV-1 RNA < 50 c/ml in the once and twicedaily groups, respectively [62].

In a 24-week, randomized, double-blind, multicenter,European comparative trial of 223 zidovudine-experiencedpatients, the addition of low dose (300 mg/day) or high dose(600 mg/day) lamivudine to zidovudine was well-toleratedand provided greater and more sustained increases inCD4+ cell counts and decreases in viral load than continuedzidovudine monotherapy [11].

In the CAESAR trial, the addition of lamivudine tozidovudine-containing treatment regimens significantly slowedthe progression of HIV disease and improved survival amongpatients with CD4+ cell counts of 25 – 250 cells/mm3

[18].Limited published data exist on the use of lamivudine in

HIV-infected pediatric patients. ACTG 300 evaluated thecombination of lamivudine plus zidovudine (3TC + ZDV)compared with either didanosine (ddI) alone or combinationzidovudine plus didanosine (ZDV + ddI) in 471 HIV-infectedchildren aged 6 weeks to 15 years. Patients receiving3TC + ZDV had a lower risk of HIV disease progression

Lamivudine

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or death than those receiving ddI alone. Weight and heightgrowth rates, CD4+ cell counts andHIV-1 RNA concentrationsfavored 3TC + ZDV [63].

PENTA 5 was a randomized controlled trial comparingthree dual NRTI combinations with or without NFV as firstART in 128 ART-naı̈ve children who were randomized toZDV + 3TC, ZDV + abacavir sulfate (ABC) or 3TC + ABC.Asymptomatic children were also randomized to NFV orplacebo; all other children received open-label NFV. Medianfollow up was 5.8 years. At week 96, in the ZDV + 3TC,ZDV + ABC and 3TC + ABC groups, mean HIV-1 RNA haddecreased by 2.4, 2.8 and 3.1 log10 c/ml, respectively, resultingin 33, 33 and 41% with HIV-1 RNA < 50 c/ml [64].

7. Safety and tolerability and regulatory affairs

Lamivudine is a member of the NRTI class for which specifictoxicities include mitochondrial toxicity, lactic acidosis,pancreatitis, peripheral neuropathy, lipoatrophy and bonemarrow toxicity. In vitro, the potencies of inhibition ofmtDNA synthesis by the NRTIs were zalcitabine (ddC)> didanosine (ddI) > stavudine (d4T) > zidovudine (ZDV)> lamivudine = abacavir = tenofovir in three different celltypes demonstrating that lamivudine is less toxic to mito-chondria among other NRTIs [65]. In fact, lamivudine hasbeen one of the most well-tolerated agents in clinical studiesamong patients with HIV or HBV infection. The mostcommonly reported adverse reactions (incidence ‡ 5%) inadults are headache, nausea, malaise and fatigue, nasal signsand symptoms, diarrhea and cough [6]. Rare adverse eventsreported with lamivudine-containing therapy include lacticacidosis and severe hepatomegaly with steatosis, severe acuteexacerbations of hepatitis in patients co-infected with HIVand hepatitis B, hepatic decompensation including fatalitiesin patients co-infected with HIV and hepatitis C receivinginterferon and ribavirin-based therapy, pancreatitis, immunereconstitution and fat redistribution [6].

Lamivudine is approved worldwide for the treatment ofHIV-1 infection and hepatitis B.

8. Expert opinion

Lamivudine in combination with other NRTIs and either aPI or an NNRTI has remained a backbone agent of choicesince its initial approval in 1995 based on its establishedefficacy and favorable safety profile in a wide variety ofpatient populations. Lamivudine is considered one of thebest-tolerated agents among all antiretroviral classes and hasbeen a main component of combination ART of pivotalregistration trials for new agents in existing or novel classesof therapy including PIs, NNRTIs, CCR5 antagonistsand integrase inhibitors. Compared to other NRTIs, lamivu-dine is not associated with anemia (as is zidovudine) ornephrotoxicity (as is tenofovir). It has better gastrointestinal

tolerability and less potential for decreased bone density,dyslipidemia, fat redistribution or long-term mitochondrialtoxicity resulting in lactic acidosis or hepatic steatosis com-pared to other NRTIs. It has utility for both initial ART aswell as for later lines of therapy due to its ability to delay theemergence of zidovudine-resistant mutants or restore zidovu-dine sensitivity. The patient continues to receive benefit fromlamivudine even after the emergence of lamivudine resistantHIV-1, due to the reduced fitness of the resistant virus. HIVcontaining M184V (the mutation selected by lamivudine)replicates less efficiently than does wild type virus, resulting inreduced plasma HIV RNA. In the absence of lamivudine, thewild type HIV becomes the majority species and the fitnessbenefit is lost.

Lamivudine is currently co-formulated with zidovudineas Combivir� (GlaxoSmithKline [GSK], Zebulon, NC,USA), with abacavir sulfate and zidovudine as Trizivir�

(GSK, Zebulon, NC, USA) and with abacavir sulfate asEpzicom� or Kivexa� (GSK, Ware, UK) outside the US.Combivir was the first approved fixed dose tablet that reduceda patient’s overall pill burden thereby improving treatmentcompliance and providing convenient twice daily dosingin the era of HAART when patients frequently received16 – 20 pills/day. Trizivir was the first complete antiretroviralregimen approved as one tablet taken twice daily to transformtherapy from multiple pills, many times a day to a moremanageable and convenient dose schedule. Although currentguidelines do not recommend first-line triple NRTI therapyconsisting of abacavir, lamivudine and zidovudine, this com-bination regimen may be used as an alternative to NNRTI- orPI-based regimens in select patients. Combining several activeantiretrovirals into one or two tablets remains a manufacturingchallenge, but is the preferred method of delivering potentcombination therapy to patients.

Given its dual activity against HIV and HBV, co-infectedpatients are frequently placed on a lamivudine-containingregimen. However, given the risk of lamivudine resistancewith long-term lamivudine monotherapy, other NRTIssuch as abacavir, zidovudine or tenofovir may be combinedwith lamivudine.

Lamivudine has also been used widely in combination withother antiretrovirals for prevention of mother-to-child trans-mission of HIV, HIV-infected infants, young children, ado-lescents and in pre- and post-exposure prophylaxis regimensdue to its favorable safety, tolerability and convenience.Lamivudine exposure in the female genital tract was amongthe highest of 11 antiretroviral drugs tested supporting its usein pre- and post-exposure prophylaxis regimens [42].

Declaration of interest

PN Kumar has been on the Speaker’s Bureau for GSK,Tibotec, Pfizer, Boehringer Ingelheim and Abbott. P Patelis an employee of GSK.

Kumar& Patel

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AffiliationPrincy N Kumar†1 MD & Parul Patel2 PharmD†Author for correspondence1Professor of Medicine and Microbiology,

Chief,

Division of Infectious Diseases,

Senior Associate Dean of Students,

Georgetown University,

110 Kober Cogan Building,

3800 Reservoir Rd NW,

Washington DC, 20007, USA

Tel: +1 202 687 6845; Fax: +1 202 687 6476;

E-mail: kumarp@gunet.georgetown.edu2Lead Clinical Development Scientist,

GlaxoSmithKline,

Five Moore Drive, P.O. Box 13398,

Research Triangle Park, NC 27709, USA

Lamivudine

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