Adefovir dipivoxil resistance

Resistance rates to adefovir dipivoxil are lower than with lamivudine, potentially allowing for prolonged treatment duration. At present, the longest trial with adefovir dipivoxil is 5 years with a resistance rate of 29%,35 compared to 5 years of lamivudine therapy with a resistance rate of 70%. 

Adefovir dipivoxil, more recently introduced, is an option in those who have unsuccessful therapy with relapse after use of interferon alpha, and/or have become lamivudine resistant. 

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... 

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. 

Adefovir dipivoxil (Hepsera) was approved for use in chronic HBV, including lamivudine-resistant HBV, in 2002. End points of therapy for HBV include disappearance of HBV DNA and elimination of HBeAg (virologic response), resolution of elevated aminotransferases (biochemical response), and improvement of liver histology. HBeAg seroconversion, an even stricter marker of viral response, denotes the loss of both HBeAg and HBV DNA and the appearance of anti-HBe. Loss of HBsAg can occur even years after completion of therapy. 

Adefovir is a nucleotide analog of deoxyadenosine monophosphate that is active against retroviruses (like HIV), herpes viruses, and hepadnaviruses. Adefovir dipivoxil 10 mg by mouth once daily for 48 weeks has been approved for use in adult patients with chronic HBV who are either treatment naive or have lamivudine-resistant... 

It is inhibitory in vitro against a range of DNA and RNA viruses, but its clinical use is limited to HBV infections. Inhibitory concentrations for HBV range from 0.2 to 1.2 xM in cell culture, and it is active against lamivudine-resistant HBV strains. Oral adefovir dipivoxil shows dose-dependent inhibition of hepad navirus replication in animal models. In vitro combinations of adefovir and lamivudine or other anti-HBV nucleosides show enhanced antihepad-navirus activity in vitro. 

Chnical use is limited to HBV infections, including lamivudine-resistant HBV strains. Oral adefovir dipivoxil shows dose-dependent inhibition of hepadnavirus replication. In vitro combinations of adefovir and lamivudine or other anti-HBV nucleosides show enhanced antihepadnavirus activity. 

MECHANISMS OF ACTION AND RESISTANCE Adefovir dipivoxil enters cells and is deesteiified to adefovir. Cellular enzymes convert adefovir to the diphosphate, which competitively inhibits viral DNA polymerases and reverse transcriptases and also serves as a chain terminator of viral DNA synthesis. Its selectivity relates to a higher affinity for HBV DNA polymerase compared with cellular polymerases. The intracellular tj j of the diphosphate is prolonged and once-daily... 

In patients with lamivudine-resistant HBV infections, adefovir dipivoxil results in sustained reductions in serum HBVDNA levels, but lamivudine alone or added to adefovir is not beneficial. 

In patients with dual HIV and lamivudine-resistant HBV infections, adefovir dipivoxil (10 mg/day) significantly reduces HBVDNA levels and also has been used successfully in patients with lamivudine-resistant HBV infections both before and following liver transplantation. The optimal duration of treatment in different populations, possible long-term effects on HBV complications, and combined use with other anti-HBV agents are under study. 

Telbivudine (3), a synthetic thymidine nucleoside analog, is the unmodified L-enantiomer of the naturally occurring D-thymidine. It prevents HBV DNA synthesis by acting as an HBV polymerase inhibitor. Within hepatocytes, telbivudine (3) is phosphorylated by host cell kinase to telbivudine-5 -triphosphate which, once incorporated into HBV DNA, causes DNA chain termination, thus inhibiting HBV replication. In this sense, telbivudine (3), like most nucleotide antiviral drugs, is a prodrug. Clinical trials have shown telbivudine (3) to be significantly more effective than lamivudine (2) or adefovir dipivoxil (4) and less likely to cause resistance. ... 

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. ... 

Drug resistance Among 65 patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B who took adefovir dipivoxil 10 mg/day for more than 1 year, adefovir resistance mutations A181V or N236T developed in 13, and were first observed after 195 weeks [12 ]. Adefovir caused no serious adverse effects. 

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