A placebo‐controlled phase I/II study of adefovir dipivoxil in patients with chronic hepatitis B virus infection

Gilson, Richard; Chopra, Kapil; Newell, A; Murray‐Lyon, Iain M.; Nelson, Mark; Rice, S J; Tedder, Richard S.; Toole, John J.; Jaffe, Howard S.; Weller, I. V. D.

doi:10.1046/j.1365-2893.1999.00182.x

Cited by 124 publications

(106 citation statements)

References 33 publications

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“…12 Adefovir dipivoxil, a nucleotide analogue with broad spectrum activity against hepadnaviruses, retroviruses, and herpesviruses, has been shown to markedly inhibit viral replication of wild-type HBV. 15,16 To date, no mutations in HBV have been associated with decreased susceptibility to adefovir dipivoxil in vitro nor has phenotypic resistance been shown in any of the clinical studies to date. In phase II study of this agent, HBeAg seroconversion has been observed in approximately 20% of patients who are treated for 12 weeks.…”

Section: Discussionmentioning

confidence: 99%

“…[10][11][12] Adefovir dipivoxil is a nucleotide analogue that has been shown to have in vitro activity against lamivudine-resistant HBV mutants and in vivo as well as in vitro activity against wild-type HBV. [13][14][15][16] Using polymerase chain reaction (PCR) mutagenesis and an enzymatic assay to measure viral sensitivity, inhibition constants were shown to change slightly in response to adefovir dipivoxil when the YMDD mutant DNA polymerases were compared with wild-type polymerase. 13,14 In these studies mutant HBV-DNA polymerases were not sensitive to famciclovir.…”

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confidence: 99%

“…In phase II clinical trials adefovir dipivoxil has also been shown to result in a greater than 1 log 10 reduction in HBV DNA after 4 weeks of treatment and a 4 log 10 reduction in HBV DNA after 12 weeks of treatment in patients infected with wild-type HBV. 15,16 Clinical testing has shown the antiviral response to 30 mg of adefovir dipivoxil to be equivalent to 60 mg after 12 weeks of treatment, and in patients followed for up to 24 weeks after discontinuation of treatment, HBeAg loss and seroconversion rates have been shown to be higher in both dose groups when compared with placebo. 16 To date, however, there have been no published reports on the use of adefovir dipivoxil to suppress HBV replication in lamivudine-resistant cases.…”

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Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants

et al. 2000

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Lamivudine has been shown to be an effective therapy for chronic hepatitis B, but resistance to this nucleoside agent is common after prolonged use. Five patients with chronic hepatitis B virus (HBV) infection developed resistance to lamivudine after 9 to 19 months of treatment. In 4 patients this occurred after liver transplantation and the remaining individual had stable cirrhosis. In each case, resistance was confirmed to be caused by one or more mutations in the HBV-DNA polymerase gene and was associated with active underlying liver disease. The patients were treated with adefovir dipivoxil in a dose of 5 to 30 mg daily. Two to 4 log 10 reductions in HBV-DNA levels were observed in 4 cases, and the fifth patient became negative by quantitative polymerase chain reaction (PCR) after retransplantation in conjunction with hepatitis B immunoglobulin (HBIg). Virologic improvement was associated with stable or declining serum alanine transaminase levels in 4 patients. HBV-DNA suppression has been sustained during a mean treatment period of 13 months (range 11 to 15 months), including 1 patient in whom lamivudine has been discontinued. Mild changes in renal function were observed during treatment in most cases but did not require early discontinuation of the drug. This study provides evidence that adefovir dipivoxil can be an effective treatment for lamivudine-resistant HBV mutants as well as wild-type HBV. (HEPATOLOGY 2000;32:129-134.)recently has been licensed in the United States, Canada, Europe, and Asia for the treatment of chronic hepatitis B. This drug has been shown to be highly effective in inhibiting hepatitis B virus (HBV) replication. [1][2][3][4] Clinical trials have provided evidence for histologic improvement as well as rates of hepatitis B e antigen (HBeAg) disappearance and seroconversion to anti-HBe that are similar to those observed with interferon alfa therapy. [1][2][3][4] One of the observations common to all of these studies, however, is the emergence of lamivudineresistant HBV mutants that undergo mutation in the HBV DNA polymerase gene. Two types of mutation have been identified to account for lamivudine resistance. 5 Mutation at codon M552 of the YMDD motif results in substitution of isoleucine for methionine (M552I). An alternate mutation at this site results in substitution of methionine by valine (M552V). The M552V mutation is accompanied by a second mutation at codon 528 that results in the substitution of leucine by methionine (L528M). In a recent analysis of data from the phase III trials of lamivudine, Atkins et al. 6 reported that resistance to lamivudine developed in 16% to 32% of patients after 1 year of treatment. 6 More recently, resistance has been shown to occur in 38% and 49% of patients after 2 and 3 years of treatment, respectively. 7,8 The natural history of hepatitis B in this situation is not yet well defined, but there have been well documented cases in which clinical and histologic progression has occurred after liver transplantation, including rapid progression to cir...

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Section: Discussionmentioning

confidence: 99%

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Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants

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“…Patients treated with 30 mg adefovir daily for 12 weeks displayed Ն99.99% decreases in median serum HBV-DNA levels from baseline. 13,14,49 A recent open-label comparative study of lamivudine and famciclovir for the treatment of chronic HBV infection showed that patients treated with 100 mg lamivudine daily for 12 weeks demonstrated Ն99% decreases in median serum HBV-DNA levels from baseline, whereas patients treated with 500 mg famciclovir daily for 12 weeks had 68% to 90% decreases in median serum HBV-DNA levels from baseline. 5 Of the 5 mutations evaluated in the present study, V555I was the most resistant mutation, showing a 6.2-fold decreased sensitivity to PCVTP.…”

Section: Discussionmentioning

confidence: 99%

In vitro evaluation of hepatitis B virus polymerase mutations associated with famciclovir resistance

et al. 2000

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Several mutations (V521L, P525L, L528M, T532S, and V555I) in the gene for hepatitis B virus (HBV) polymerase have been identified in HBV isolated from patients that displayed break-through viremia during famciclovir treatment. To determine whether these mutations cause phenotypic resistance to famciclovir, we compared the inhibition constants (K i ) of penciclovir triphosphate (PCVTP, the active metabolite of famciclovir) for recombinant wild-type and mutant HBV polymerases containing these mutations. In in vitro enzymatic assays, the V555I mutation displayed the most resistance (with K i increased by 6.2-fold) to PCVTP. The V521L and L528M mutations showed moderately decreased sensitivity to PCVTP (K i increased by G3-fold). We also analyzed the cross-resistance profiles of these variants for adefovir and lamivudine, two other antiviral agents that also inhibit DNA replication by HBV polymerase. All 5 famciclovir-associated mutations were sensitive to adefovir diphosphate (ADVDP) in in vitro enzymatic assays (F2.3-fold decreased sensitivity). The V521L, L528M, and T532S mutations were also sensitive to lamivudine triphosphate (LAMTP); however, the P525L and V555I mutations displayed moderately decreased sensitivity to LAMTP in enzymatic assays (3.6-fold decreased sensitivity). The lamivudine-resistant mutations M552I, M552V, and L528M؉M552V, which were previously shown to display 8-to 25-fold resistance to LAMTP, were less resistant (I3.1-fold) to PCVTP. (HEPATOLOGY 2000;31:219-224.)Hepatitis B viral infection is a major cause of acute and chronic hepatitis, cirrhosis, and hepatocellular carcinoma, and it is one of the 10 most common causes of death worldwide. 1 Current treatment regimens rely primarily on interferon alfa therapy. However, interferon has limited efficacy, is expensive, requires parenteral administration, and is associated with frequent and unpleasant side effects. Nucleoside or nucleotide analogs, which inhibit DNA replication through hepatitis B virus (HBV) polymerase, represent a new class of promising anti-HBV therapeutics. In addition to lamivudine, 2-9 which was approved recently for the treatment of hepatitis B infection in the United States, several nucleoside and nucleotide analogs including famciclovir 5,10,11 and adefovir dipivoxil 12-14 are currently being evaluated in late stage clinical trials. These compounds have been shown to be well tolerated and can produce rapid and marked decreases in serum HBV-DNA levels.Famciclovir is the oral prodrug of penciclovir, which has to be converted to penciclovir triphosphate by cellular enzymes to become an active inhibitor against HBV polymerase by competing with the natural substrate deoxyguanosine triphosphate (dGTP). 15 Famciclovir was originally approved for the treatment of herpes simplex virus and herpes zoster virus. 16,17 Later, famciclovir was shown to have activity against human and duck hepatitis B viruses in enzymatic and cell culture assays and in animal models of infection. 15,[18][19][20][21] Clinical studies subsequently showed...

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“…Inhibition of HBV replication by adefovir dipivoxil is usually rapid, in the range of a 4 log10 reduction in HBV DNA after 12 weeks of treatment. 1 To date, no adefovir-resistant mutation has been reported. We report events associated with its use in a liver transplant recipient with recurrent lamivudine-resistant chronic hepatitis B.…”

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Predominance of pre-S1 mutated hepatitis B virus in a patient following treatment with adefovir dipivoxil

Villa

Boarino

Grottola

et al. 2003

Liver Transplantation

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A liver transplant recipient reinfected with a lamivudineresistant mixed wild-type/pre-S1-deleted hepatitis B virus (HBV) strain and rescued with adefovir dipivoxil was still HBV DNA positive after more than 1 year of therapy. Analysis of serum HBV DNA, amplified by polymerase chain reaction and directly sequenced by dideoxy nucleotide chain-termination method, showed that adefovir inhibited the wild type, but not the pre-S1-deleted HBV. Predominance of the pre-S1-deleted strain over wild type after adefovir treatment suggests that either adefovir inhibited the wild type more effectively or the pre-S1 mutant replicates more efficiently. The normality of liver condition confirms that to exert its pathogenic effect, the pre-S1-deleted strain requires the presence of wild-type virus. A defovir dipivoxil is a nucleotide phosphonate analogue that has strong activity against hepatitis B virus (HBV) infection and represents an effective alternative to lamivudine when drug-induced YMDD mutations occur. Inhibition of HBV replication by adefovir dipivoxil is usually rapid, in the range of a 4 log10 reduction in HBV DNA after 12 weeks of treatment. 1 To date, no adefovir-resistant mutation has been reported. We report events associated with its use in a liver transplant recipient with recurrent lamivudine-resistant chronic hepatitis B.The patient, an anesthesiologist, experienced several needle-stick exposures during his professional lifetime. HBV infection was diagnosed in 1986. In 1990, liver biopsy showed chronic hepatitis with moderate activity. At that time, alanine aminotransferase (ALT) levels constantly ranged between 4 and 6 times greater than the upper limit of normal (ULN). HBV DNA was positive by dot blot hybridization. The patient was started on recombinant interferon (IFN), 9 million units thrice weekly. He initially responded, but after 3 months, he experienced a sharp hepatitic flare. ALT levels increased to 15 times greater than the ULN. These levels were maintained for more than 2 months when IFN therapy was discontinued.Retrospective sequence analysis, after cloning of the polymerase chain reaction (PCR) products of HBV DNA, showed pure wild-type virus before starting IFN therapy. At the time of hepatitic flare, 6 months after beginning IFN therapy, a mutant HBV population appeared. This mutant population first bore a 42-bp deletion, then a double of 42 and 81 nucleotides in the pre-S1 region, which became predominant and constant. Associated with the deletions, a C3 T mutation at the second codon after the ATG of the pre-S2 region occurred, which gave rise to a stop codon preventing pre-S2 transcription and increasing intermediate HBV replicative forms. 2,3 The 123-bp deletion of the pre-S1 region, being multiple of three nucleotides, did not alter the open reading frame of the polymerase region that bore, as single alterations, a YVDD mutation in the samples after lamivudine treatment (Fig. 1).The mutant population gradually became predominant in comparison to the wild-type one, which nevertheless alwa...

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A placebo‐controlled phase I/II study of adefovir dipivoxil in patients with chronic hepatitis B virus infection

Cited by 124 publications

References 33 publications

Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants

Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants

In vitro evaluation of hepatitis B virus polymerase mutations associated with famciclovir resistance

Predominance of pre-S1 mutated hepatitis B virus in a patient following treatment with adefovir dipivoxil

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