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

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

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Adefovir

Last Update: February 15, 2016.

OVERVIEW

Introduction

Adefovir dipivoxil is an acyclic nucleotide analogue of adenosine used either alone or in combination with other agents as therapy of chronic hepatitis B. Adefovir does not appear to be a significant cause of drug induced liver injury, but initiation of therapy and sudden withdrawal of therapy can induce a transient exacerbation of the underlying hepatitis B.

Background

Adefovir dipivoxil (bis-pom PMEA) is an acyclic nucleotide analog and prodrug of adefovir (a def' oh vir). The dipivoxil moiety is hydrolyzed after absorption, and adefovir is phosphorylated intracellularly to its active form, adefovir triphosphate, which competes with deoxyadenosine triphosphate for incorporation into the growing HBV DNA strand, causing inhibition of the viral DNA polymerase and chain termination. Adefovir is indicated for the treatment of chronic hepatitis B as a single agent and with lamivudine for lamivudine-resistant HBV infection. Adefovir was approved by the FDA in 2002 as therapy for hepatitis B. Adefovir is available generically and under the brand name Hepsera in 10 mg tablets. The recommended dose of adefovir is 10 mg orally once daily in adults and children age 12 years and older. The dose should be adjusted for renal impairment. Adefovir has minimal activity against human immunodeficiency virus (HIV) infection and is considered contraindicated in patients with HBV-HIV coinfection. Recently, adefovir has been largely replaced by tenofovir which has a similar mechanism and spectrum of activity, but is approximately 30 times more potent against HBV. Side effects of adefovir include asthenia and renal injury which is marked by increases in serum creatinine levels, hypophosphatemia, hypouricemia and renal tubular acidosis.

Hepatotoxicity

Serum aminotransferase elevations are common during or after therapy of hepatitis B, but appear to be due to exacerbations of the underlying HBV infection rather than hepatotoxicity. Sudden withdrawal of adefovir therapy can lead to an acute flare of hepatitis as viral levels suddenly rise. These withdrawal flares are usually transient and self-limited, but in rare instances are symptomatic and severe and can lead to death or need for liver transplantation. Instances of moderate serum aminotransferase elevations early during treatment have been described in clinical trials, but these elevations are usually transient and asymptomatic and are found in up to 25% of persons who start nucleoside analogue therapy of hepatitis B. Finally, development of antiviral resistance can be followed by a flare of the underlying hepatitis B as HBV DNA levels rise. Antiviral resistance to adefovir is rare during the first 1 to 2 years of therapy, but increasing rates are found with long-term therapy.

Adefovir has not been associated with cases of lactic acidosis with hepatic steatosis and liver failure. Tenofovir, a nucleotide analogue similar to adefovir, has been associated with isolated cases of lactic acidosis, but only in combination with other antiretroviral agents that are more closely linked to this syndrome. Because adefovir is considered contraindicated in HIV infection (it has weak anti-HIV activity), it is not used in combination with typical antiretroviral drugs. There have been no convincing cases of lactic acidosis or of clinically apparent liver injury with symptoms or jaundice due to adefovir.

Likehood score: E (unlikely cause of clinically apparent, idiosyncratic liver injury).

Mechanism of Injury

The apparent absence of significant hepatotoxicity from adefovir may be due to its minimal hepatic metabolism and rapid urinary excretion. In vitro, adefovir demonstrates little inhibitory activity against mitochondrial polymerase gamma.

Outcome and Management

The mild-to-moderate ALT elevations associated with initiating adefovir use are usually asymptomatic and transient. Due to the high percentage of patients who have flares of hepatitis B after discontinuation of adefovir, serum aminotransferase testing should be monitored for several months and antiviral therapy resumed if symptoms or jaundice arise or serum aminotransferases remain significantly above baseline (pretreatment) levels. Patients who develop antiviral resistance to adefovir can have significant flares of hepatitis B and should be switched to or have added another agent with a different profile of resistance.

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

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

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

CASE REPORT

Case 1. Flare of hepatitis B accompanying development of adefovir resistance.

[NIH Case: Adefovir-Lamivudine #6]

A 56 year old man with chronic hepatitis B and previous therapy with interferon and lamivudine was treated with adefovir (10 mg daily). He took no other medications and did not drink alcohol. He had no symptoms of hepatitis, but appeared to have Gilbert’s syndrome with intermittently elevated total bilirubin levels, but normal direct fractions. He was positive for HBsAg and HBeAg in serum and HBV DNA levels were high. Molecular testing revealed evidence of lamivudine-resistant virus (rtM204V/rtL180M). ALT levels were only modestly elevated (Table). A liver biopsy showed moderate histological activity and bridging hepatic fibrosis. With adefovir therapy, serum HBV DNA levels decreased by only 3 to 4 log10 copies per mL and ALT levels improved minimally. Liver histology did not change. He remained asymptomatic and had no other medical problems. During the third year of therapy, HBV DNA levels began to rise towards pretreatment values and serum ALT levels increased five-fold. Molecular testing showed presence of the typical adefovir-resistant mutation in the HBV polymerase gene: rtN236T. Switching therapy to tenofovir led to prompt decrease in HBV DNA levels and improvements in ALT values.

Key Points

Medication:Adefovir (10 mg daily)
Pattern:Hepatocellular
Severity:1+ (aminotransferase elevations without jaundice)
Latency:3 years
Recovery:After switching to tenofovir therapy
Other medications:None

Laboratory Values

Time After StartingTime After StoppingAST (U/L)Alk P (U/L)Bilirubin (mg/dL)HBV DNA (copies/mL)Other
055951.7456,000,000Liver biopsy
6 months461051.6892,000
1 year48902.7489,000Liver biopsy
2 years451081.7120,000
3 years331142.2121,506
3.7 years43941.2132,026,000rtN236T mutation
4 years205981.931,349,600
Switched to tenofovir therapy (300 mg daily)
2 months*2 months611082.51,715
6months*6 months271292.5<58
5 years*5 years251301.5<10
Normal Values <42 <115 <1.2

*Time after switching to tenofovir

Comment

Adefovir therapy of chronic hepatitis B is associated with a low rate of antiviral resistance during the first 1 to 2 years of treatment, but a somewhat high rate of poor initial response (as in this patient). Antiviral resistant rates increase to 17% to 28% after 3 to 4 years of treatment. Development of virological breakthrough is commonly followed by a flare in the underlying hepatitis. In this patient, the flare was mild and the adefovir-resistant virus was successfully suppressed by tenofovir therapy. These features make monotherapy with adefovir problematic in chronic hepatitis B and it is now rarely used.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Adefovir – Hepsera®

DRUG CLASS

Antiviral Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NUMBERMOLECULAR FORMULASTRUCTURE
Adefovir 106941-25-7 C8-H12-N5-O4-P
Adefovir Chemical Structure

ANNOTATED BIBLIOGRAPHY

References updated: 15 February 2016

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    (Review of hepatotoxicity of antiviral agents; mentions the potential of severe flares of disease upon withdrawal of therapy in chronic hepatitis B).
  • Acosta EP, Flexner C. Antiviral agents (nonretroviral). In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1593-1622.
    (Textbook of pharmacology and therapeutics).
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  • Marcellin P, Change TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, Jeffers L, et al.; Adefovir Dipivoxil 437 Study Group. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med 2003; 348: 808-16. [PubMed: 12606735]
    (Controlled trial of adefovir vs placebo for 48 weeks in 515 patients with HBeAg-positive chronic hepatitis B: ALT elevations >10 times ULN occurred in 9% of adefovir vs 19% placebo recipients; in the adefovir group, no patient had jaundice or needed to stop therapy for ALT elevations).
  • Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, Marcellin P, et al.; Adefovir Dipivoxil 438 Study Group. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 2003; 348: 800-7. Erratum in: N Engl J Med 2003; 348: 1192. [PubMed: 12606734]
    (Controlled trial of adefovir vs placebo for 48 weeks in 185 patients with HBeAg-negative chronic hepatitis B; one placebo- but no adefovir-treated patient had severe flare of hepatitis).
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    (45 year old woman with HIV-HCV coinfection developed jaundice and lactic acidosis on tenofovir [8 weeks], didanosine and stavudine [long term] [bilirubin 12.6 mg/dL, ALT 157 U/L], with progressive liver failure and death; role of tenofovir vs didanosine and stavudine uncertain).
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    (63 year old man with HIV and HCV developed fatal lactic acidosis 1.5 years after starting didanosine-tenofovir-lopinavir-ritonavir regimen, with pancreatitis, multiorgan failure and death; liver injury not mentioned).
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  • Marcellin P, Chang TT, Lim SG, Sievert W, Tong M, Arterburn S, Borroto-Esoda K, et al. Long-term efficacy and safety of adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. Hepatology 2008; 48: 750-8. [PubMed: 18752330]
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  • Terrault NA, Bzowej NH, Chang KM, Hwang JP, Jonas MM, Murad MH. AASLD guidelines for treatment of chronic hepatitis B. Hepatology 2016; 63: 261-83. [PMC free article: PMC5987259] [PubMed: 26566064]
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