Tenofovir Disoproxil Fumarate
Adis, North Shore, Auckland, New Zealand. Drugs
(Impact Factor: 4.34).
11/2009; 69(16):2245-56. DOI: 10.2165/10482940-000000000-00000
Tenofovir disoproxil fumarate (tenofovir DF) is an orally administered ester prodrug of tenofovir, a nucleotide reverse transcriptase inhibitor that shows potent in vitro activity against both hepatitis B virus (HBV) and HIV-1.
▴ As a component of antiretroviral combination therapy regimens, tenofovir DF is well established in the treatment of adults with HIV-1 infection. Tenofovir DF, administered once daily, is also used in the treatment of adults with chronic hepatitis B (CHB) [the main focus of this profile].
▴ In CHB, the efficacy of tenofovir DF against HBV has been evaluated in two large randomized, phase III clinical studies in hepatitis B e antigen (HBeAg)-negative or HBeAg-positive adults, with compensated liver function. The trials (planned duration 8 years) were double-blind for the first 48 weeks; thereafter, patients received open-label tenofovir DF. Results at 48 and 96 weeks are available.
▴ In these studies, at week 48, a significantly greater proportion of recipients of tenofovir DF 300 mg once daily than oral adefovir dipivoxil 10 mg once daily achieved a complete response (primary endpoint). A complete response was defined as a reduction from baseline in plasma HBV DNA level to <400 copies/mL and histological improvement (reduction of 2 or more points in Knodell necroinflammatory score without worsening of fibrosis).
▴ The efficacy of tenofovir DF in the treatment of CHB was also demonstrated over a 96-week treatment period in both studies.
▴ Tenofovir DF was generally well tolerated by adults with CHB in the two phase III trials.
Available from: Ben Berkhout
- "The pharmaceuticals tenofovir and adefovir are nucleotide-analogues for treatment of hepatitis B virus (HBV) infection , . Monotherapy using adefovir frequently caused viral breakthrough due to the appearance of resistance mutations , . "
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Resistance of the reverse transcriptase (RT) of hepatitis B virus (HBV) to the tenofovir nucleotide drug has not been observed since its introduction for treatment of hepatitis B virus (HBV) infection in 2008. In contrast, frequent viral breakthrough and resistance has been documented for adefovir. Our computational study addresses an inventory of the structural differences between these two nucleotide analogues and their binding sites and affinities to wildtype (wt) and mutant RT enzyme structures based on in silico modeling, in comparison with the natural nucleotide substrates.
Tenofovir and adefovir only differ by an extra CH3-moiety in tenofovir, introducing a center of chirality at the carbon atom linking the purine group with the phosphates. (R)-Tenofovir (and not (S)-tenofovir) binds significantly better to HBV-RT than adefovir. “Single hit” mutations in HBV-RT associated with adefovir resistance may affect the affinity for tenofovir, but to a level that is insufficient for tenofovir resistance. The RT-Surface protein gene overlap in the HBV genome provides an additional genetic constraint that limits the mutational freedom required to generate drug-resistance. Different pockets near the nucleotide binding motif (YMDD) in HBV-RT can bind nucleotides and nucleotide analogues with different affinities and specificities.
The difference in binding affinity of tenofovir (more than two orders of magnitude in terms of local concentration), a 30x higher dosage of the (R)-tenofovir enantiomer as compared to conformational isomeric or rotameric adefovir, and the constrained mutational space due to gene overlap in HBV may explain the absence of resistance mutations after 6 years of tenofovir monotherapy. In addition, the computational methodology applied here may guide the development of antiviral drugs with better resistance profiles.
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ABSTRACT: Telbivudine, the unmodified L-enantiomer of the naturally occurring nucleoside D-thymidine, is a potent synthetic nucleoside analogue. It acts as a hepatitis B virus (HBV) polymerase inhibitor and preferentially inhibits HBV second strand (DNA-dependent) compared with first strand (RNA-dependent) DNA synthesis.
▲ More telbivudine than lamivudine recipients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B and similar proportions of telbivudine or lamivudine recipients with HBeAg-negative disease achieved a therapeutic response at 52 weeks in the large 2-year GLOBE trial. In a phase III trial in Chinese patients, greater reductions in serum HBV DNA occurred with telbivudine than lamivudine at 52 weeks.
▲ Reductions in serum HBV DNA at 24 weeks were greater with telbivudine than adefovir in the 1-year switching trial. A lower residual viral load at 52 weeks was seen in patients who received telbivudine or who switched from adefovir to telbivudine at 24 weeks than in patients receiving adefovir.
▲ In the 1-year lamivudine switching trial in patients with serum HBV DNA levels >3 log10 copies/mL despite having received prior treatment with lamivudine for a mean of ≈7 months, those randomised to telbivudine therapy achieved greater reductions in serum HBV DNA levels at 24 weeks than patients randomised to continue lamivudine therapy.
▲ Telbivudine was generally well tolerated and most adverse events were of mild or moderate severity. The incidence of severe ALT flares with telbivudine was half that seen with lamivudine at both 52 and 104 weeks in the GLOBE trial.
Available from: future-science.com
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