Hepatitis adefovir dipivoxil

Adefovir in its prodrug form, adefovir dipivoxil, is indicated in the treatment of chronic HBV infections (chronic hepatitis B), where, if administered orally as a single dose of lOmg per day, HBV DNA load is reduced significantly (>31ogio) over a 1- or 2-year period (Hadziyannis et al. 2005). 

Persons with confirmed chronic hepatitis B should be evaluated for treatment, which may include interferon, pegylated interferon, lamivudine, adefovir dipivoxil, or entecavir. The drug of choice for chronic hepatitis B depends on the patient s past medical history, aminotransferase level, HBV DNA level, and most importantly, HBeAg status. 

Patients infected with HBeAg-negative chronic hepatitis B have a significant response while on adefovir dipivoxil, but the response is not sustained after treatment discontinuation. Serum ALT levels normalized in 72% of patients treated for 48 weeks compared to 29% who received placebo. Additionally, 51% had undetectable HBV DNA levels with adefovir dipivoxil, whereas none achieved this in the placebo arm.20,27,32... 

National Institute for Health and Clinical Excellence. Hepatitis B (chronic) - adefovir dipivoxil and peginter-feron alpha-2a. Technology appraisal TA096. [2006], Available from URL www.nice.org.uk National Institute for Health and Clinical Excellence. Hepatitis C peginterferon and ribavirin. Technology appraisal TA106. [2006]. Available from URL WWW. nice. org. uk... 

Several anti-HBV agents have anti-HIV activity as well, including lamivudine, adefovir dipivoxil, and tenofovir. Emtricitabine, an antiretroviral NRTI, is under clinical evaluation for HBV treatment. Because NRTI agents may be used in patients co-infected with HBV and HIV, it is important to note that acute exacerbation of hepatitis may occur upon discontinuation or interruption of these agents. 

Adefovir dipivoxil is well tolerated. A dose-dependent nephrotoxicity has been observed in clinical trials, manifested by increased serum creatinine with decreased serum phosphorous and more common in patients with baseline renal insufficiency and those receiving high doses (60 mg/d). Other potential adverse effects are headache, diarrhea, asthenia, and abdominal pain. As with other NRTI agents, lactic acidosis and hepatic steatosis are considered a risk owing to mitochondrial dysfunction. No clinically important drug-drug interactions have been recognized to date. Pivalic acid, a by-product of adefovir dipivoxil metabolism, can esterify free carnitine and result in decreased carnitine levels. However, it is not felt necessary to administer carnitine supplementation with the low doses used to treat patients with HBV (10 mg/d). 

NICE (National Institute for Health and Clinical Excellence) (2006) Guidance on the use of adefovir dipivoxil and pegylated interferon alpha-2b for the treatment of chronic hepatitis B. Available at http //www.nice.org.uk/guidance/TA96 [Accessed 2 July 2008],... 

C. L., Schiff, E. Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus. Gastroenterology 2004 126 81-90... 

Peters, M.G., Hann, H.W., Martin, P., Heathcote, E.X, Bnggisch, P., Rubin, R., Bourliere, M., Kowdley, K., Trepo, C., Gray, DJi., Sullivan, M., Kleber, K., Ebrahimi, R., Xiong, S., Brosgart, C.L. Adefovir dipivoxil alone or in combination with lamivudine in patients with lami-vudine-resistant chronic hepatitis B. Gastroenterology 2004 126 91-101... 

Werle, B., Cinquin, K., Marcellin, P., Pol, S., Maynard, M., Trepo, C., Zoulim, F. Evolution of hepatitis B viral load and viral genome sequence during adefovir dipivoxil therapy. J. Viral Hepat. 2003 11 74-83... 

Benhamou Y, Bochet M, Thibault V, Calvez V, Fievet MH, Vig P, Gibbs CS, Brosgart C, Fry J, Namini H, Katlama C, Poynard T. Safety and efficacy of adefovir dipivoxil in patients co-infected with HIV-1 and lamivudine-resistant hepatitis B virus an open-label pilot study. Lancet 2001 358(9283) 718-23. 

Hadziyannis S, Tassopoulos N, Heathcote E, Chang T> Kitis G, Rizzetto M, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-negative chronic hepatitis B. N Engl J Med 2003 348 800-7. 

M. Tsiang, J. F. Rooney, J. J. Toole, and C. S. Gibbs, Biphasic clearance kinetics of hepatitis B virus from patients during adefovir dipivoxil therapy. Hepatology 29 1863-1869 (1999). 

Dando T, Plosker G. Adefovir dipivoxil A review of its use in chronic hepatitis B. Drugs 2003 63 2215-2234. 

Adefovir is an antiviral agent that inhibits hepatitis B virus (HBV) DNA polymerase (reverse transcriptase) by competing with the natural substrate deoxyadenosine triphosphate and by causing DNA chain termination after its incorporation into viral DNA. Adefovir is indicated in the treatment of chronic hepatitis B in adults with evidence of active viral replication and evidence of persistent elevations in serum aminotransferases or histologically active disease. Adefovir dipivoxil (9-[2-[bis[(pivaloyloxy)methoxy] phosphinyl]methoxyl]ethyl]adenine, bis-POM PMEA) is a diester prodrug of adefovir, an acyclic phosphonate nucleotide analog of adenosine monophosphate. 

Adefovir dipivoxil is an orally active prodrug indicated for the treatment of chronic hepatitis B. The drug is hydrolyzed by extracellular esterases to produce adefovir, which in turn is phosphorylated by adenylate kinase to adefovir diphosphate, which inhibits HBV DNA polymerase. Incorporation of adefovir into viral DNA also leads to DNA chain termination. As shown in Figure 43.9, adefovir dipivoxyl is activated in two steps involving an esterase that exposes a free phosphate group (adefovir), followed by addition of a second phosphate by adenylate kinase to form adefovir diphosphate, the active form of the drug. 

Adenine itself was successfully incorporated into a number of pharmaceuticals, Adefovir dipivoxil, also known as bis-POM PMEA, with trade names Preveon and Hepsera, is used for the treatment of hepatitis B and herpes simplex virus infection. It is an orally administered nucleotide analog as a reverse transcriptase inhibitor (NRTI). Reverse transcriptase is an enzyme crucial to viral production. A second NRXI that contains adenine is Tenofovir disoproxil fumarate (TDF), which has been used in the treatment of HIV/AIDS and hepatitis B. TDF is a prodrug of tenofovir (also known as PMPA) designed to improve absorption and cell permeability of the active moiety under the trade name Viread. Both adefovir dipivoxil and TDF are marketed by Gilead Sciences. 

The acyclic nucleoside phosphonate, 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA), also known as Adefovir [1], can be considered as an analogue of (2 -deoxy)adenosine 5 -monophosphate ((d)AMP ) [2]. PMEA has excellent antiviral properties [1] and in the form of its bis(pivaloyloxymethyl)ester, Adefovir dipivoxil, it has recently been approved by the US Food and Drug Administration (FDA) for the treatment [3] of hepatitis B patients these people suffer from an infection of aDNAvirus. 

Adefovir dipivoxil (4) was initially developed as a treatment for HIV, but the FDA in 1999 rejected the drug due to concerns about the severity and frequency of kidney toxicity when dosed at 60 or 120 mg, respectively. However, 4 was effective at a much lower dose of 10 mg for the treatment of chronic hepatitis B in adults with evidence of active viral replication and either evidence of persistent elevations in serum alanine aminotransferases (primarily ALT) or histologically active disease. It works by blocking reverse transcriptase, an enzyme that is crucial for the HBV to reproduce in the body. Overall, the efficacy of 4 against wild-type and lamivudine (2)-resistant HBV and the delayed emergence of 4-resistance during monotherapy contribute to the durable safety and efficacy observed in a wide range of chronic hepatitis B patients. ... 

Wong T, Girgis CM, Ngu MC, Chen RC, Emmett L, Archer KA, Seibel MJ. Hypo-phosphatemic osteomalacia after low-dose adefovir dipivoxil therapy for hepatitis B. J Clin Endocrinol Metab 2010 95(2) 479-80. 

Tamori A, Enomoto M, Kobayashi S, Iwai S, Morikawa H, Sakaguchi H, Habu D, Shiomi S, Imanishi Y, Kawada N. Add-on combination therapy with adefovir dipivoxil induces renal impairment in patients with lamivudine-refractory hepatitis B virus. J Viral Hepat 2010 17(2) 123-9. 

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