Lamivudine and intron a combination treatment in patients with chronic hepatitis B infection

Heathcote, Jenny; Sw, Schalm; Cianciara, J; Farrell, G; Feinmann, V; Shermann, M; Dhillon, AP; Moorat, AE; Gray, DF

doi:10.1016/s0168-8278(98)80380-2

Cited by 40 publications

(28 citation statements)

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“…The number of patients studied here is relatively small, but the comparability in HBeAg responses (loss or seroconversion) between 12 months of lamivudine therapy and 4 months of interferon therapy is also supported by the results of a large, controlled trial. 15 Moreover, lamivudine treatment can achieve HBeAg responses in interferonrefractory patients, as we observed among 5 of 9 previous interferon nonresponders.…”

Section: Discussionmentioning

confidence: 51%

Extended lamivudine retreatment for chronic hepatitis B: Maintenance of viral suppression after discontinuation of therapy

Dienstag¹,

Schiff²,

Mitchell³

et al. 1999

Hepatology

188

128

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In patients with chronic hepatitis B, brief lamivudine therapy suppresses hepatitis B virus (HBV) DNA but results infrequently in sustained losses of virus replication posttreatment. We evaluated treatment response and its posttreatment durability during up to 18 months of lamivudine therapy (100 mg/d) in 24 patients who had hepatitis B e antigen (HBeAg) despite 1 to 3 months of prior therapy. Therapy was to be stopped after HBeAg loss or seroconversion (acquisition of antibody to HBeAg); posttreatment monitoring continued for 6 months. During therapy, which was well tolerated, HBV DNA became undetectable in all evaluable patients, accompanied by reduced alanine transaminase (ALT) activity. The cumulative 18-month confirmed loss of HBeAg during therapy was 9 of 24 (38%) and seroconversion was 5 of 24 (21%). Therapy was discontinued after HBeAg loss/seroconversion in 7 patients, and Chronic hepatitis B virus (HBV) infection occurs in approximately 5% of the world' s population and is among the top 10 causes of death. Although interferon alfa has been approved as therapy for chronic hepatitis B, such treatment is suboptimal, yielding clinical benefit in a minority of patients. Lamivudine is an oral dideoxynucleoside that inhibits reverse transcription by causing chain termination of nascent viral DNA in human immunodeficiency virus (HIV) and HBV infection. 1 As reported previously, phase-II dose-ranging trials in North American and western European patients with chronic hepatitis B included daily doses of 5 to 600 mg administered for 1 to 6 months. 2-4 Therapy was well tolerated, doses of 100 mg or more suppressed serum HBV DNA levels consistently during therapy, and no significant advantage was identified for doses above 100 mg. 3,4 A sustained response posttreatment, however, defined as the loss of hepatitis B e antigen (HBeAg) and failure of HBV DNA to reappear after discontinuation of therapy, occurred in only 4% to 12% of patients in these dose-ranging studies. In a recently completed placebo-controlled phase-III trial involving 358 Chinese patients, Lai et al. 5 reported that 12 months of lamivudine therapy at a dose of 100 mg/d was associated with histological improvement in 67% of patients and HBeAg seroconversion in 16%, which is significantly better than response rates observed in concurrent placebo controls. This study in Asian patients, however, did not address treatmentstopping criteria; regardless of HBeAg status at the end of 12 months of therapy, all patients were enrolled in a continuingtreatment follow-up study. 5 In the present study, we wished to determine whether prolonged lamivudine therapy in Western patients would be safe and tolerable and result in loss of HBeAg and HBeAg seroconversion in a higher proportion of patients compared with the shorter dosing regimens studied previously. We also sought to determine whether lamivudine therapy could be withdrawn after HBeAg loss or HBeAg seroconversion. Therefore, we undertook an extended-treatment trial in previously Abbreviations: HBV, hepatitis...

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Section: Discussionmentioning

confidence: 51%

Extended lamivudine retreatment for chronic hepatitis B: Maintenance of viral suppression after discontinuation of therapy

Dienstag¹,

Schiff²,

Mitchell³

et al. 1999

Hepatology

188

128

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“…One patient (case 1) had evidence for histologic improvement after 10 months of adefovir dipivoxil treatment. A second patient (case 3) showed marked diminution in hepatitis B core antigen staining in liver tissue in association with a 4 log 10 reduction in serum HBV DNA. A decline in serum ALT level was observed in 4 cases and was striking in 2 patients (cases 2 and 4).…”

Section: Resultsmentioning

confidence: 96%

“…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.…”

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confidence: 99%

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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“…Possible future regimens may include antiviral single agents or combinations to decrease viral load, immunomodulatory therapy to eliminate residual intracellular virus, followed by therapeutic immunization to induce loss of the carrier state. Although 2 international, multicenter trials 13,27 have not shown significantly improved responses with a combination of lamivudine and interferon for 6 months, these do not necessarily predict results with other combinations. Several other regimens, [28][29][30][31] including 2 or more nucleoside analogues or a nucleoside analogue plus immunomodulatory therapy, are being considered.…”

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confidence: 97%

Hepatitis B therapy: The plot thickens

Malik

Lee

1999

Hepatology

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Chronic hepatitis B virus (HBV) infection is a continuing global public health problem, with the World Health Organization estimating that chronic carriers worldwide will number 400 million by the year 2000. 1 The virus responsible for hepatitis B was identified in 1966. 2 Therapy for the past 10 years has consisted of alfa interferon, to which about 30% of patients respond, as defined by loss of hepatitis B e antigen (HBeAg) 3 and a decrease in serum DNA levels to undetectable by conventional hybridization assays. 4 Responses are wellmaintained in 85% of cases. 5 In 60% to 70% of patients, a flare of alanine transaminase (ALT) activity occurs during or shortly after interferon treatment, thought to represent immune-mediated clearance of HBV-infected hepatocytes. The drawbacks of interferon include the necessity for parenteral administration, its side-effect profile, and the fact that only selected patients are candidates for this treatment, 6-8 namely, those with a low pretreatment HBV DNA (Ͻ200 pg/mL) and high serum transaminase (Ͼ100 IU/L). For patients who do not meet these criteria, response rates are less than 5%. 9 For the latter group and others, including immunosuppressed patients and decompensated cirrhotics, 10 effective treatment has not been available until recently.The new generation of antivirals is based on advances in our understanding of HBV DNA replication, including the similarity of this process to the replication of retroviruses such as human immunodeficiency virus (HIV). HBV is a partially double-stranded DNA virus that replicates by means of a DNA polymerase that also serves as a reversetranscriptase in the synthesis of viral DNA from a pregenomic RNA template. As a reverse-transcriptase, this enzyme has extensive homology to the retroviral reverse-transcriptases. The HBV genome localizes to the nucleus after hepatocyte infection and is converted to covalently closed circular DNA (cccDNA). Transcription of cccDNA yields an RNA intermediate that moves to the cytoplasm, where the viral DNA polymerase, acting as a reverse-transcriptase, catalyzes the synthesis of a new relaxed circular DNA.Many of the reverse transcriptase inhibitors active against HIV have also proven effective against HBV. Famciclovir, adefovir, emtricitabine, and BMS-200475 are being tested: these are oral agents and are more potent inhibitors of hepatitis B replication than is alfa interferon. The largest experience available to date is with lamivudine. Efficacy and safety data are available from approximately 700 patients who took lamivudine, 100 mg daily, for 1 year as part of 3 placebo-controlled phase-III clinical trials. 11-13 Normalization of ALT occurred in about 40% to 70% of patients in the lamivudine group; this rate was significantly higher than that of patients treated with placebo (P Ͻ .001 for all studies). HBeAg loss occurred in 17% to 33% of lamivudine-treated patients versus 11% to 13% with placebo, and 16% to 18% of lamivudine recipients achieved seroconversion of HBeAg to anti-HBe. HBV DNA suppression ...

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Lamivudine and intron a combination treatment in patients with chronic hepatitis B infection

Cited by 40 publications

References 0 publications

Extended lamivudine retreatment for chronic hepatitis B: Maintenance of viral suppression after discontinuation of therapy

Extended lamivudine retreatment for chronic hepatitis B: Maintenance of viral suppression after discontinuation of therapy

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

Hepatitis B therapy: The plot thickens

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