, Volume 58, Issue 1, pp 101-141
Date: 10 Oct 2012

Lamivudine

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Summary

Abstract

Lamivudine is a deoxycytidine analogue that is active against hepatitis B virus (HBV). In patients with chronic hepatitis B, lamivudine profoundly suppresses HBV replication.

Clinically significant improvements in liver histology and biochemical parameters were obtained with lamivudine in double-blind, randomised, trials in hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B and compensated liver disease. After 52 weeks of treatment, relative to placebo (≤25%), significantly more Chinese (56%) or Western patients (52%) treated with lamivudine 100 mg/day had reductions of ≥2 or more points in Knodell necro-inflammatory scores. Moreover, significantly fewer lamivudine 100 mg/day than placebo recipients had progressive fibrosis in liver biopsies (≤5 vs ≥15%) and fewer lamivudinethan placebo-treated patients progressed to cirrhosis (1.8 vs 7.1%). More lamivudine 100 mg/day than placebo recipients acquired antibodies to HBeAg after 52 weeks (16 vs 4% in Chinese patients and 17 vs 6% in Western patients). ALT levels normalised in significantly more lamivudine than placebo recipients enrolled in these trials.

In HBeAg-negative, HBV DNA positive patients with compensated liver disease enrolled in a double-blind, randomised study, HBV DNA levels were suppressed to below the limit of detection (< 2.5 pg/ml) and ALT levels normalised in 63% and 6% of patients treated with lamivudine 100 mg/day or placebo for 24 weeks. Clinically significant improvements in liver histology were obtained in 60% of patients treated with lamivudine for 52 weeks in this study.

Lamivudine 100 mg/day for 52 weeks produced similar or significantly greater improvements in liver histology and ALT levels than 24 weeks’ treatment with lamivudine plus interferon-α.

In liver transplant candidates with chronic hepatitis B and end-stage liver disease, lamivudine 100 mg/day alone, or in combination with hepatitis B immune globulin, generally suppressed HBV replication and appeared to protect the grafted liver from reinfection. Lamivudine 100 mg/day suppressed viral replication and improved liver histology in liver transplant recipients with recurrent or de novo chronic hepatitis B. Lamivudine 300 or 600 mg/day reduced HBV replication in HIV-positive patients.

The incidence of adverse events in patients with chronic hepatitis B and compensated liver disease treated with lamivudine 100 mg/day or placebo for 52 to 68 weeks was similar. 3.1- to 10-fold increases in ALT over baseline occurred in 13% of patients during treatment with lamivudine 100 mg/day or placebo for 52 weeks. Post-treatment ALT elevations were more common in lamivudine than placebo recipients; however, these generally resolved spontaneously; ≤1.5% of lamivudine- or placebo-treated patients experienced hepatic decompensation.

Conclusion: Lamivudine inhibits HBV replication, reduces hepatic necro-inflammatory activity and the progression of fibrosis in patients with chronic hepatitis B, ongoing viral replication and compensated liver disease including HBeAg-negative patients. The drug also suppresses viral replication in liver transplant recipients and HIV-positive patients. Thus, lamivudine is potentially useful in a wide range of patients with chronic hepatitis B and ongoing viral replication.

Pharmacodynamic Properties

Lamivudine is a deoxycytidine analogue with antiviral properties. Lamivudine is phosphorylated by host cell kinases to a triphosphate moiety that is active against hepatitis B virus (HBV). The concentration of lamivudine required to reduce HBV DNA concentrations by 50% (EC50) and 90% (EC90) in the supernatant of cultures of human hepatocellular carcinoma cell lines (2.2.15 and HB611 cells) was 0.008 to 0.1 μmol/L and 0.16 to 0.9 μmol/L, respectively. EC50 and EC90 values for lamivudine were 2.7- to 5.75-fold lower than those for penciclovir (the active metabolite of famciclovir).

Lamivudine significantly suppressed HBV replication in a chimaeric mouse-human model of chronic hepatitis B infection. After 4 days of treatment with lamivudine 0.5mg twice daily, mean HBV DNA levels were reduced by 97% and only 14% of mice had detectable HBV DNA levels [limit of detection (LOD) < 5 × 103 copies/ml]. In contrast 90% of control mice had detectable HBV DNA levels. HBV DNA levels increased substantially within 5 days of the cessation of treatment.

Lamivudine-resistant HBV has been isolated from some patients with chronic hepatitis B during treatment with lamivudine. In lamivudine-resistant clinical isolates a point mutation in a highly conserved motif [Tyr-Met-Asp-Asp (YMDD)], in which valine (M552V) or isoleucine (M552I) is substituted for methionine, has been consistently identified. A second mutation (L528M), in which methionine replaces leucine 24 amino acids upstream, has been identified in some isolates containing M552V and M552I and confers cross-resistance to famciclovir. Lamivudine-resistant HBV does not appear to be cross-resistant to adefovir. The EC50 of 1 clinical isolate increased 45-fold after acquiring M552V In addition, the EC50 of lamivudine in HepG2 cells transfected with viral constructs containing M552V was 153-, 550- and 3010-fold greater for HBV containing M552V, M552I and L528M plus M552V, respectively, than for that containing wild-type HBV. Clinical observations suggest that replication is slower in HBV with YMDD variant motifs than in wild-type virus.

Four and 14% of 285 Chinese patients, respectively, acquired resistant YMDD variant genotypes after 9 and 12 months of lamivudine therapy. However, histo-logical responses were not affected by the presence of YMDD variant HBV.

Lamivudine does not interfere with human DNA synthesis and exhibits little cytotoxicity in human cell lines. The 3′-5′ exonuclease function of human DNA polymerase γ (mitochondrial DNA polymerase) excised lamivudine 5′-mono-phosphate incorporated during chain termination assays and lamivudine (0.01 to 0.03 μ,mol/L) did not appreciably inhibit DNA synthesis in intact mitochondria. Moreover, no morphological or functional changes in hepatocellular mitochondria were detected in liver biopsy specimens from patients treated with lamivudine 25 to 300 mg/day.

Cellular immune responsiveness increased during treatment with lamivudine in patients with chronic hepatitis B. Statistically significant increases in proliferation of T cells obtained from 12 patients with chronic hepatitis B occurred during treatment with lamivudine 100 mg/day and were associated with suppression of HBV DNA levels.

Pharmacokinetic Properties

Lamivudine is well absorbed after oral administration (mean bioavailability 86 to 88%). The drug is not extensively bound to plasma proteins (36%), distributes into total body fluid (volume of distribution 1.3 L/kg) and crosses the placenta (the drug is present in amniotic fluid), where concentrations appear to equilibrate between the maternal and foetal circulation.

In 6 patients with chronic hepatitis B receiving lamivudine 100 mg/day, the mean maximum plasma concentration (Cmax) of lamivudine at steady state was 1.1 mg/L, the mean area under the plasma concentration versus time curve from 0 to 24 hours (AUC24) was 4.72 mg/L · h and the mean terminal elimination half-life was 6.2 hours. In paediatric patients (2 to 12 years of age) with chronic hepatitis B, lamivudine 3 mg/kg once daily provided a steady state Cmax and AUC of ≈1.5 mg/L and ≥4 mg/L · h.

The major route of elimination of lamivudine is renal excretion. In patients with moderate/severe renal dysfunction [i.e. those with creatinine clearance <3 L/hr (<50 ml/min)] elimination of lamivudine is significantly retarded and the dosage should be adjusted. Dosage modifications are not required in patients with decompensated liver disease.

Therapeutic Potential in Chronic Hepatitis B

Lamivudine has been evaluated in randomised, placebo-controlled studies in immunocompetent patients with chronic hepatitis B and compensated liver disease, including HBeAg-negative, HBV DNA-positive patients. The drug has also been studied in HBV DNA-positive liver transplant candidates with chronic hepatitis B. The effect of lamivudine in HIV-positive patients with chronic hepatitis B has been described. Histological improvement in liver biopsy specimens was the primary or secondary end-point in several studies. Markers of hepatitis B replication, hepatitis B serology, and normalisation of ALT levels were also used as end-points in these studies.

The results of dose ranging studies with lamivudine in patients with chronic hepatitis B and compensated liver disease suggest that daily dosages ≥100 mg/day are optimal for this indication.

Clinically significant improvements in liver histology were obtained with lamivudine in 2 double-blind, randomised trials in HBeAg-positive immunocompetent patients with chronic hepatitis B and compensated liver disease. Significantly more Chinese (56%) or Western patients (52%) treated with lamivudine 100 mg/day than placebo recipients (≤25%) had clinically significant reductions (defined as a reduction of ≥ 2 points) in Knodell necroinflammatory scores after 52 weeks of treatment. Worsening fibrosis was detected in ≥15% of placebo recipients, but in ≤ 5% of lamivudine 100 mg/day recipients during these 2 studies.

Significantly more lamivudine 100 mg/day than placebo recipients converted from HBeAg-positive to positive for antibodies to HBeAg (anti-HBe) during 52 weeks of treatment in these 2 studies (16 vs 4% in Chinese patients and 17 vs 6% in Western patients). Among Chinese patients randomised to further double-blind treatment with lamivudine 100 mg/day, the proportion of patients who serocon-verted from HBeAg-positive to anti-HBe was 27% and 33%, respectively, after 2 and 3 years.

Lamivudine generally reduced ALT levels in patients enrolled in these trials. In Chinese patients in whom ALT levels were elevated at baseline, normalisation of ALT levels occurred in 72% of those treated with lamivudine 100 mg/day, but in only 24% of placebo recipients. Similarly, ALT normalisation was more common in Western patients treated with lamivudine 100 mg/day or placebo for 52 weeks (41 vs 7%).

Lamivudine 100 mg/day reduced HBV DNA, HBeAg and ALT levels and produced improvements in liver histology in Japanese patients with chronic hepatitis B.

Lamivudine was generally effective in suppressing HBV replication and ameliorating liver disease in HBeAg-negative patients (presumed to harbour precore mutant HBV) with chronic hepatitis B and compensated liver disease. Significantly more patients treated with lamivudine 100 mg/day in a randomised double-blind study achieved the primary efficacy end-point, HBV DNA levels < 2.5 pg/ml and ALT levels within the normal range, than placebo-treated patients after 24 weeks (63 vs 6%). Of patients enrolled in this trial who had evaluable liver biopsies at baseline and after 52 weeks of treatment with lamivudine 100 mg/day, 60% had a reduction of ≥2 or more points in the Knodell necroinflamma-tory score. These results show that the effectiveness of lamivudine in HBeAgnegative patients with chronic hepatitis B is generally similar to that in HBeAg-positive patients.

Histological responses were reported in 2 studies in which patients with chronic hepatitis B and compensated liver disease received lamivudine 100 mg/day alone for 52 weeks or combined with interferon-α 30 million units (MU) per week for 16 weeks. However, liver biopsies were obtained at the end of treatment with lamivudine and 28 or 36 weeks after completion of therapy with lamivudine plus interferon-α or interferon-a monotherapy, which makes interpretation of the results difficult. Among patients receiving lamivudine monotherapy for 52 weeks in these 2 studies, 52 and 38% of patients had clinically significant reductions in Knodell necroinflammatory scores. In 1 study, in which only patients refractory to interferon-α were enrolled, a significantly greater proportion of patients treated with lamivudine 100 mg/day experienced clinically significant improvement in liver histology at 52 weeks than those treated with lamivudine 100 mg/day alone for 8 weeks and then combined with interferon-α for 16 weeks.

A pooled analysis of 3 clinical trials revealed the frequency of progression to cirrhosis to be 1.8, 7.1 and 9.5%, respectively, after 1 year of treatment with lamivudine 100 mg/day, placebo and interferon-α.

Lamivudine 150 mg/day plus interferon-α 13.5 MU/week was more effective than ganciclovir 750 mg/day plus interferon-α 13.5 MU/week in suppressing HBV replication during a 26-week study. HBV DNA levels rebounded after discontinuation of antiviral therapy.

Lamivudine 100 mg/day was more effective than famciclovir 500mg 3 times daily in suppressing HBV replication in patients with chronic hepatitis B. 78% of lamivudine recipients, but only 8% of famciclovir recipients experienced a reduction of >2 log10 in HBV DNA levels or were HBV DNA negative (LOD ≤2.5 pg/ml) after 12 weeks’ of treatment (p < 0.0001).

When started before transplantation, lamivudine 100 or 150 mg/day suppressed HBV DNA levels in most liver transplant candidates with chronic hepatitis B and end-stage liver disease. Hepatitis B core antigen (HBcAg) was not detected in biopsy specimens obtained from ≥50% of patients after transplantation in 4 small studies (n = 4 to 38). Most patients were hepatitis B surface antigen-and HBeAg-negative after transplantation.

No evidence of hepatitis B replication (e.g. HBV DNA or HBeAg in serum) was evident in liver transplant recipients treated with lamivudine 100 mg/day before transplantation and lamivudine 100 mg/day plus hepatitis B immune globulin (HBIg) during and after transplantation.

In 52 liver transplant recipients with recurrent or de novo chronic hepatitis B, lamivudine 100 mg/day for 52 weeks suppressed HBV DNAbelow the LOD (≤1.6 pg/ml) in 60% of patients and improved liver histology in 51% of patients. YMDD variant HBV was detected in 14 patients, 5 of whom experienced clinical deterioration due to the progression of hepatic disease.

Lamivudine was effective in reducing HBV DNA replication in HIV-positive patients with chronic hepatitis B. In 30 patients with high rates of HBV replication (HBV DNA >5 ng/L and HBeAg-positive) prior to treatment only 15% (4 of 27) remained HBV DNA-positive (by PCR) after 52 weeks of lamivudine 300 or 600 mg/day. Similarly, none of 10 patients with low rates of HBV DNA replication (HBV DNA <5 ng/L and HBeAg-negative) were HBV DNA-positive at the end of treatment compared with 6 at baseline. A retrospective analysis showed 27 of 66 (41%) HBV DNA-positive patients became HBV DNA-negative (assay not described) during treatment with lamivudine 300 mg/day for HIV infection compared with 3 of 17 (18%) placebo recipients.

In children aged 2 to 12 years with chronic hepatitis B, lamivudine oral solution 3 mg/kg/day (approximately twice the dosage used in adults with chronic hepatitis B) produced maximal antiviral effects (99.9% inhibition of viral replication).

Tolerability

The incidence of adverse events in lamivudine- or placebo-treated patients was similar in a pooled analysis of 4 randomised, double-blind trials in patients with hepatitis B. One or more drug-related adverse events were reported by 40 and 45% of patients, respectively, treated with lamivudine 100 mg/day (n = 416) or placebo (n = 200) for 52 to 68 weeks in these trials. ALT levels increased by ≥3.1-fold over baseline in 13% of patients during treatment with lamivudine 100 mg/day or placebo for 52 weeks.

Lamivudine was better tolerated than interferon-α in comparative trials. The frequency of malaise and fatigue, fever and chills, muscle pain, nausea and vomiting, hair loss or depressive disorders was 2 to 8 times more common in patients treated with interferon-α, alone or in combination with lamivudine, than lamivudine 100 mg/day.

Substantial elevations in ALT levels have occurred during treatment and follow-up in patients receiving lamivudine or placebo in randomised trials. Although ALT elevations were more common in lamivudine-than placebo-treated patients after discontinuation of treatment, ALT elevations generally resolved spontaneously and the incidence of hepatic decompensation was rare (i.e. ≤1.5%) in both groups.

Dosage and Administration

Lamivudine 100mg given once daily is the recommended dosage in HIV-negative patients with chronic hepatitis B, ongoing viral replication and compensated liver disease. In HIV-positive patients the dosage is 150mg twice daily in combination with other antiretroviral agents. The drug may be taken with or without food. Dosage adjustments are recommended in patients with chronic hepatitis B and clinically significant renal dysfunction.

Various sections of the manuscript reviewed by: P. Andreone, Ambulatorio di Epatologia, Servizio di Semeiotica Medica, Università di Bologna, Bologna, Italy; M. Buti, Liver Unit, Hospital General Universitario Valle Hebron, Barcelona, Spain; F.J. Carrilho, Department of Gastroenterology, Clinical Hepatology Branch, University of Sāo Paulo School of Medicine, Sāo Paulo, Brazil; E. De Clercq, Rega Institute for Medical Research, Minderbroedersstraat, Leuven, Belgium; C. Cursaro, Ambulatorio di Epatologia, Servizio di Semeiotica Medica, Università di Bologna, Bologna, Italy; R.A. de Man, Department of Internal Medicine II, Erasmus University, Rotterdam, The Netherlands; B.G. Gazzard, Chelsea and Westminster Hospital, London, England; A. Gramenzi, Ambulatorio di Epatologia, Servizio di Semeiotica Medica, Università di Bologna, Bologna, Italy; J. Heathcote, Division of Gastroenterology, The Toronto Hospital and University of Toronto, Toronto, Ontario, Canada; P. Honkoop, Department of Internal Medicine II, Dijkzigt Hospital, Rotterdam, The Netherlands; N.W.Y. Leung, Department of Medicine, Prince of Wales Hospital, Hong Kong; D. Mutimer, The Liver and Hepatobiliary Unit, Queen Elizabeth Hospital, Birmingham, UK; L. Naesens, Rega Institute for Medical Research, Minderbroedersstraat, Leuven, Belgium; J. Neyts, Rega Institute for Medical Research, Minderbroedersstraat, Leuven, Belgium; R.F. Schinazi, Veterans Affairs Medical Center and Emory University, Decatur, Georgia, USA; T. Shaw, Victorian Infectious Diseases Reference Laboratory, Melbourne, Victoria, Australia; N.C. Tassopoulos, Western Attica General Hospital, Athens, Greece; T.L. Wright, Gastroenterology Unit, Veterans Affairs Medical Center, San Francisco, California, USA.

Data Selection

Sources: Medical literature published in any language since 1966 on lamivudine, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand), Medline and EMBASE. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: AdisBase, Medline and EMBASE search terms were ‘lamivudine’, ‘2-3-dideoxy-3-thiacytidine’, ‘3-TC’, ‘3TC’, ‘BCH-189’, ‘BCH-790’, ‘BTC’, ‘GR-103665’, ‘GR-109714’, ‘GR-109714X’, ‘NGPB-21’, ‘SDDC’ and ‘hepatitis-B’. Searches were last updated 31May 1999.
Selection: Studies in patients with hepatitis B who received lamivudine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Hepatitis B, lamivudine, pharmacodynamics, pharmacokinetics, therapeutic use.