Combination Therapy with Famciclovir and Interferon‐α for the Treatment of Chronic Hepatitis B

Marques, Adriana; Lau, Daryl T.Y.; McKenzie, Robin; Straus, Stephen E.; Hoofnagle, Jay H.

doi:10.1086/314430

Cited by 33 publications

(19 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…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. …”

mentioning

confidence: 99%

Hepatitis B therapy: The plot thickens

Malik

Lee

1999

Hepatology

View full text Add to dashboard Cite

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 ...

show abstract

mentioning

confidence: 99%

Hepatitis B therapy: The plot thickens

Malik

Lee

1999

Hepatology

View full text Add to dashboard Cite

show abstract

“…Unfortunately, the viral load increased once again in four of the patients after stopping the medication and three of them remained HBeAg positive at all times during the study. 73 In vitro studies support the use of two or more nucleoside analogues for HBV infection. The combination of lamivudine with either interferon alpha or penciclovir significantly enhances the antiviral effectiveness of these agents against HBV replication in 2.2.15 cell culture, an HBV-producing human hepatoblastoma cell line, the result of which has been shown to predict antiviral responses in vivo.…”

Section: Hepatitis B Combination Therapymentioning

confidence: 99%

Advances in the treatment of chronic hepatitis B virus infection

Marques

Straus

1998

Rev. Med. Virol.

View full text Add to dashboard Cite

“…6 Preliminary clinical trials of newer nucleoside analogues in combination with IFN-␣ have been similarly disappointing, perhaps because a large proportion of patients in these trials had failed IFN-␣ therapy. 26,27 On the other hand, preclinical results suggest that the newer anti-HBV nucleoside analogues are at least additive in their effects and that antagonistic interactions are rare. [28][29][30] As the number of safe and effective anti-HBV drugs increases, the means to assess, quantify, and compare drug efficacy and drug interactions in a standardized manner will become an important issue in both preclinical tests and clinical trials.…”

Section: Combination Chemotherapy and Drug Resistancementioning

confidence: 99%

“…Whether the best approach will involve using additional nucleosides or adding immunomodulators to nucleoside combinations is not yet known. Preliminary reports from ongoing phase III clinical trials of IFN-␣ in combination with lamivudine 26 or famciclovir 27 have already appeared and suggest that either combination is effective with long-term administration. The next logical step may be to initiate trials of triple therapy with IFN-␣, lamivudine, and famciclovir.…”

Section: Future Prospectsmentioning

confidence: 99%