Review of Oral Therapeutic Options for the Treatment of Chronic Hepatitis B: Entecavir, Adefovir Dipivoxil, and Lamivudine

By Jessica C. Song, MA, PharmD, Assistant Professor of Pharmacy Practice, University of the Pacific, Stockton, CA, and Pharmacy Clerkship and Coordinator, Santa Clara Valley Medical Center, Section Editor, Managed Care, is Associate Editor for Infectious Disease Alert

Jessica Song reports no consultant, stockholder, speaker’s bureau, research, or other financial relationships with companies having ties to this field of study.

Treatment of chronic Hepatitis B is directed at suppressing viral replication, reducing hepatitis (necroinflammatory) activity, slowing progression of fibrotic disease, and rendering patients noninfectious. At present, 3 oral antiviral agents, entecavir, adefovir dipivoxil, and lamivudine, are FDA-approved for the treatment of chronic hepatitis B, with entecavir receiving FDA approval in March 2005. This article will: 1) review the pharmacology, pharmacokinetics, and FDA indications of entecavir, adefovir, and lamivudine, 2) review the safety and efficacy of the 2 drugs, and 3) review the drug interactions and dosage of the 3 nucleoside analogs.

Pharmacology

Entecavir is a guanosine nucleoside analog with activity against hepatitis B virus (HBV) polymerase that undergoes phosphorylation to the active triphosphate form. Entecavir competes with the natural substrate deoxyguanosine triphosphate and, therefore, inhibits all 3 activities of HBV DNA Polymerase: 1) positive strand synthesis of HBV DNA, 2) base priming, and 3) reverse transcription of the negative strand from the pregenomic messenger RNA.

Adefovir dipivoxil is a diester prodrug of adefovir, an acyclic nucleotide analog with activity against human HBV. Following conversion of this prodrug to adefovir in the gastrointestinal tract, cellular kinases phosphorylate adefovir to the active metabolite, adefovir diphosphate. Adefovir diphosphate competes with the natural substrate deoxyadenosine triphosphate and thus inhibits HBV DNA Polymerase. Incorporation of adefovir diphosphate into viral DNA results in DNA chain termination.

Lamivudine, a synthetic nucleoside analog, undergoes intracellular phosphorylation to form lamivudine triphosphate. DNA chain termination occurs following the incorporation of lamivudine triphosphate into viral DNA by HBV polymerase.

Metabolism and Elimination

Following oral administration, adefovir dipivoxil undergoes rapid conversion to adefovir, which constitutes 45% of the dose recovered in urine (over 24 hours at steady state). Adefovir and entecavir are renally excreted by a combination of active tubular secretion and glomerular filtration, with steady state urinary recovery of unchanged drug ranging from 62% to 73% of the administered dose of entecavir. Lamivudine undergoes minimal metabolism, as the majority of the drug is eliminated unchanged in urine by active organic cationic secretion.

Adverse Effects/Warnings

The most commonly reported adverse events from clinical trials of entecavir were: headache (2%-4%), fatigue (1%-3%), nausea (< 1%), and dizziness (< 1%). Adefovir dipivoxil is generally well tolerated, with the following adverse events occurring in 3% of patients taking this drug: asthenia, headache, abdominal pain, nausea, flatulence, diarrhea, and dyspepsia. The most common adverse events experienced by patients taking lamivudine for treatment of chronic HBV (5% incidence in clinical trials) were malaise/fatigue, fever or chills, ear/nose/throat infections, sore throat, nausea/vomiting, abdominal pain, diarrhea, myalgia, arthralgia, headache, and skin rash.

Since severe lactic acidosis and severe hepatomegaly with steatosis have been reported with the use of other nucleoside analogs in HIV infection, the FDA mandated the manufacturers of entecavir, adefovir dipivoxil, and lamivudine to place black box warnings in the monographs for the 3 agents. It is believed currently that this syndrome is caused by defective mitochondrial DNA replication. Active triphosphate forms of nucleoside analog reverse transcriptase inhibitors (NRTIs) and nucleotide reverse transcriptase inhibitors inhibit mitochondrial DNA polymerase-, thereby impairing the synthesis of mitochondrial enzymes responsible for generating ATP by oxidative phosphorylation of glucose and fatty acids. Defective oxidation of glucose and fatty acids may result in increases in intracellular lactate and fatty acids.6 The incidence of lactic acidosis associated with adefovir or lamivudine is not reported in the prescribing information. However, a retrospective review (1996-2000) conducted by Bonnet and colleagues reported an incidence of 0.9/1000 NRTI-treated patient years (HIV-infected patients receiving lamivudine, didanosine, stavudine, or zidovudine).2 How does this compare with the incidence of metformin-associated lactic acidosis? The prescribing information for metformin cites an incidence of 0.03 cases per 1000 patient years, and postmarketing data from Canada and Europe show an incidence of 9 and 1 to 15 cases per 100,000 person-years, respectively.3 Numerous case reports have implicated stavudine, zidovudine, didanosine, and lamivudine in causing lactic acidosis in HIV-positive patients. Obesity, impaired renal function (CrCl<70 mL/min), and cumulative NRTI exposure may increase the risk of lactic acidosis.4

Clinical Efficacy

At present, 3 oral drugs have been approved by the FDA for use in the management of chronic HBV infection, including entecavir (Baraclude), lamivudine (Epivir-HBV ), and adefovir dipivoxil (Hepsera). Emergence of resistance (via YMDD mutation) has been associated with lamivudine therapy, developing in 15-32% of patients after one year of therapy and in up to 69% of patients after 5 years of therapy.6 Viral resistance appears to be less likely to develop during adefovir dipivoxil therapy, as one study showed that the mutant rtN236T (or rtA181V) was identified in 3.9% of chronic hepatitis B patients at 144 weeks’ follow-up. Similarly, the emergence of entecavir resistance has been shown to be a rare occurrence, as none of 550 nucleoside-naïve patients receiving 0.5 mg entecavir were shown to exhibit resistance during 48 weeks of treatment. Moreover, 1% of lamivudine-refractory patients receiving 1 mg entecavir experienced resistance-related rebound.7 In vitro studies have demonstrated that susceptibility to entecavir is maintained for recombinant HBV genomes encoding for adefovir resistance. Additional in vitro data has shown that HBV isolates from lamivudine-refractory patients failing entecavir treatment retained susceptibility to adefovir.

Clinical trials of adefovir dipivoxil and lamivudine have shown similar degrees of improvement in liver histology, with 53-64% and 52-56% of adefovir dipivoxil- and lamivudine-treated patients achieving a minimum of a 2-point reduction in the Knodell score, respectively.5,8-14 HBeAg serocon-version rates were 11-12% and 16-18%, respectively, for adefovir dipivoxil- and lamivudine-treated patients in recent clinical trials. A comparable proportion of patients achieved normalization of ALT levels following treatment with adefovir dipivoxil or lamivudine, as shown by normalization rates of 31-72% and 41-72%, respectively. In contrast, Phase III clinical trials have shown the superior efficacy of entecavir compared with that of lamivudine, in regards to improvement in Knodell necroinflammatory scores (55-72%), proportion of patients achieving undetectable HBV DNA levels (up to 90%), proportion of patients achieving ALT normalization (61-78%), and decline in HBV DNA levels.11-12 Tables 1, 2, and 3 summarize key findings from recent clinical trials evaluating the efficacy of entecavir, adefovir dipivoxil, and lamivudine in the treatment of chronic HBV infection.

Recent studies have confirmed the efficacy of adefovir dipivoxil 10 mg/day and entecavir 1 mg/day against lamivudine-resistant HBV, with no difference in efficacy between adefovir dipivoxil monotherapy and combination therapy (adefovir dipivoxil/continuation of lamivudine), or between entecavir monotherapy and continued lamivudine treatment. Table 4 summarizes the results from clinical trials that evaluated the efficacy of adefovir dipivoxil and entecavir in the management of lamivudine-resistant chronic HBV infection.13-14

Table 1
Clinical Trials of Adefovir for the Management of Chronic HBV infection (52-week duration)
 
Marcellin17,a
Hadziyannis20,b
Adefovirc (n=171) Placebo (n=167) p-value Adefovir (n=123) Placebo (n=61) p-value
Histological improvementd 53% 25% <0.001 64% 33% <0.001
HBeAg
seroconversion
12% 6% <0.049 Not evaluated Not evaluated Not evaluated
Mean ↓ in HBV DNA (#log copies/mL) 3.57 0.98 <0.001 3.91 1.35 <0.001
Normalization of ALT 48% 16% <0.001 72% 29% <0.001
  1. Patient demographics: 35-37% White; 58-60% Asian; 2-5% Black. Inclusion: HBeAg-positive chronic HBV patients (compensated liver disease).
  2. Patient demographics: 67% White; 4% Black; 29% Asian. Inclusion: HBeAg-negative chronic HBV patients (compensated liver disease).
  3. Includes the number of patients receiving adefovir 10 mg/day.
  4. Decrease of at least 2 points in Knodell necroinflammatory score.

Table 2
Clinical Trials of Lamivudine for the Management of Chronic HBV infection (52-week duration)
 
Dienstag21,a
Lai22,bN
Lamivudine (n=66) Placebo (n=71) p-value Lamivudine n=143 Placebo (n=72) p-value
Histological improvementc 52% 23% <0.001 56% 25% <0.001
HBeAg
seroconversion
17% 6% 0.04 16% 4% 0.02
Undetectable HBV DNA (10 pg/mL) 44% 16% <0.001 Not evaluated Not evaluated Not evaluated
Normalization of ALT 41% 7% <0.001 72% 24% <0.001
  1. Patient demographics: 56-59% White; 17-24% Asian; 15-18% Black. Inclusion: HBeAg-positive chronic HBV patients (compensated liver disease)..
  2. Patient demographics: 100% Chinese. Inclusion: HBeAg-positive chronic HBV patients (compensated liver disease).
  3. Decrease of at least 2 points in Knodell necroinflammatory score.

Table 3
Clinical Trials of Entecavir for the Management of Chronic HBV Infection (52-week duration)
 
Chang23,a
Lai24,b
Entecavirc Lamivudine p-value Entecavird Lamivudine p-value
Histological improvementc 72% 62% <0.05 70% 61% <0.05
HBeAg
seroconversion
21% 18% Not evaluated Not evaluated Not evaluated Not evaluated
Undetectable HBV DNA (<300 copies/mL) 67% 36% <0.05 90% 72% <0.05
Mean ↓ in HBV DNA (#log copies/mL) 6.86 5.39 <0.05 5.04 4.53 <0.05
Normalization of ALT 68% 60% <0.05 78% 71% <0.05

Table 4
Clinical Trials with Lamivudine-Resistant Chronic Hepatitis B Patients (52-week duration)
 
Sherman25,a
Perrillo26,b
Entecavir (n=286) Lamivudinec (n=286) p-value (n=286) Group Ad (n=94) Group Be (n=40) p-value (Group A)
Histological improvementf 55% 28% <0.01 Not evaluated Not evaluated Not evaluated
Mean change in DAVGg (# log copies/mL) Not evaluated Not evaluated Not evaluated Not evaluated Not evaluated Not evaluated
HBV DNA < 300 copies/mL 19% 1% <0.0001 Not evaluated Not evaluated Not evaluated
HBV DNA < 105 copies/mL Not evaluated Not evaluated Not evaluated 85% combined;
11% lamivudine
92% <0.01
HBeAg seroconversion 8% 3% 8% combined;
2% lamivudine
4% NS
Normalization of ALT 61% 15% <0.0001 31% combined;
6% lamivudine
53% 0.0002

Dosing of Entecavir
CrCl (mL/min) Usual Dose (not lamivudine-refractory) Lamivudine-Refractory
≥ 50 mL/min 0.5 mg po qday 1 mg po qday
30-49 0.25 mg po qday 0.5 mg po qday
10-29 0.15 mg po qday 0.3 mg po qday
< 10, hemodialysis or peritoneal dialysis 0.05 mg po qday (administer after hemodialysis) 0.1 mg po qday

Dosing of Adefovir Dipivoxil
CrCl ≥ 50 mL/min CrCl 20-49 mL/min CrCl 10-19 mL/min Hemodialysis patients Peritoneal dialysis patients
10 mg po qday 10 mg po q 48 h 10 mg po q 72 h 10 mg po q 7 d following dialysis no data

Dosing of Adefovir Lamivudine
CrCl ≥ 50 mL/min CrCl 30-49 mL/min CrCl 15-29 mL/min CrCl 5-14 mL/min < 5 mL/min
100 mg po qday 100 mg first dose, then 50 mg po qday 100 mg first dose, then 25 mg po qday 35 mg first dose, then 15 mg po qday 35 mg first dose, then 10 mg po qday

Drug Interactions

The potential for CYP450 (Cytochrome P450)-mediated interactions is low for entecavir, as it does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP2B6, CYP2E1, and CYP3A4. Entecavir is not an inducer of CYP1A2, CYP2C9, CYP2C19, CYP3A4, CYP3A5, and CYP2B6, and it is not a substrate of the CYP450 enzyme system. The potential for CYP450-mediated interactions with adefovir dipivoxil is low, as this agent does not inhibit CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. Moreover, adefovir is not a substrate of CYP1A2, CYP2C9, CYP2C19, CYP2D6, or CYP3A4. However, the manufacturer advises precautions with concurrent use of adefovir dipivoxil with known nephrotoxic agents.

Since lamivudine is predominantly eliminated by active organic cation secretion, concomitant administration with other drugs renally secreted by the organic cation transport system (eg, trimethoprim), may increase lamivudine toxicity. Lamivudine and zalcitabine in combination is not recommended because the 2 agents may inhibit the intracellular phosphorylation of one another.

References

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  2. Bonnet F, et al. Severe Lactic Acidosis in HIV-Infected Patients Treated with Nucleosidic Reverse Transcriptase Analogs: A Report of 9 Cases. Rev Med Interne. 2003;24:11-16.
  3. Stang M, et al. Incidence of Lactic Acidosis in Metformin Users. Diabetes Care. 1999;22:925-927.
  4. Bonnet F, et al. Risk Factors for Lactic Acidosis in HIV-Infected Patients Treated with Nucleoside Reverse-Transcriptase Inhibitors: A Case-Control Study. Clin Infect Dis. 2003;36:1324-1328.
  5. Marcellin P, et al. Adefovir Dipivoxil for the Treatment of Hepatitis B E Antigen-Positive Chronic Hepatitis B. N Engl J Med. 2003;348:808-816.
  6. Lai CL, et al. Viral Hepatitis B. Lancet. 2003;362:2089-2094.
  7. Colonno RJ, et al. Entecavir (ETV) Resistance is Not Observed in Nucleoside-Naïve Subjects and is Observed Infrequently By Week 48 in Lamivudine Refractory Subjects with Chronic HBV Infection. Poster Presented at: 40th Annual Meeting of the European Association for the Study of the Liver; April 13-17,2005;Paris,France. Poster 590.
  8. Hadziyannis SJ, et al. Adefovir Dipivoxil for the Treatment of Hepatitis B E Antigen-Negative Chronic Hepatitis B. N Engl J Med. 2003;348:800-807.
  9. Dienstag JL, et al. Lamivudine as Initial Treatment for Chronic Hepatitis B in the United States. N Engl J Med. 1999;341:1256-1263.
  10. Lai CL, et al. A One-Year Trial of Lamivudine for Chronic Hepatitis B. N Engl J Med. 1998;339:61-68.
  11. Chang TT, et al. Entecavir is Superior to Lamivudine for the Treatment of HBeAg(+) Chronic Hepatitis B: Results of a Phase III Study ETV-022 in Nucleoside-Naïve Patients [Abstract]. In: Abstracts and Itinerary Planner of The Liver Meeting: 55th Annual Meeting of the American Association for the Study of Liver Disease; October 29-November 2, 2004; Boston, MA. Abstract 70.
  12. Shouval D, et al. Entecavir Demonstrates Superior Histologic and Virologic Efficacy Over Lamivudine in Nucleoside-Naïve HBeAg(-) Chronic Hepatitis B: Results of Phase III trial ETV-027 [abstract]. In: Abstracts and Itinerary Planner of The Liver Meeting: 55th Annual Meeting of the American Association for the Study of Liver Disease; October 29-November 2, 2004; Boston, MA. Abstract LB-07.
  13. Sherman M, et al. Entecavir is Superior to Continued Lamivudine for the Treatment of Lamivudine-Refractory, HBeAg(+) Chronic Hepatitis B: Results of Phase III Study ETV-026 [abstract]. In: Abstracts and Itinerary Planner of The Liver Meeting: 55th Annual Meeting of the American Association for the Study of Liver Disease; October 29-November 2, 2004; Boston, MA. Abstract 1152.
  14. Perrillo R, et al. Adefovir Dipivoxil Added to Ongoing Lamivudine in Chronic Hepatitis B with YMDD Mutant Hepatitis B Virus.Gastroenterology. 2004;126:81-90.