Antiviral treatment of chronic hepatitis B virus infection: Improvement in liver disease with interferon and adenine arabinoside

Scullard, George; Andres, Ljudevit L.; Greenberg, Harry B.; Smith, Joseph L.; Sawhney, Vinod K.; Neal, Elizabeth A; Mahal, Anmol S.; Pópper, Hans; Merigan, Thomas C.; Robinson, William S.; Gregory, Peter B.

doi:10.1002/hep.1840010306

Cited by 94 publications

(23 citation statements)

References 8 publications

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“…[20][21][22][23][24][25][26][27][28][29] In addition, histological assessments of patients in other studies of lamivudine have shown that liver biopsy features improve significantly during lamivudine-induced suppression of HBV replication. 5,30,31 Further controlled trials of prolonged lamivudine treatment are in progress to define the efficacy and safety of lamivudine therapy and maintenance of virological responses after drug withdrawal.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…IFN treatment reduces hepatitis B virus-specific DNA-polymerase activity and other viral markers in the serum of patients with chronic hepatitis (22). Several viral markers also disappear or decrease in hepatic tissue (21). Other workers, however, observed no effect of IFN treatment except for a transient decrease in DNA-polymerase activity (26).…”

mentioning

confidence: 99%

Effect of Interferon on the Production of HBsAg and Induction of an Antiviral State in Human Hepatoma Cell Line PLC/PRF/5

Nakajima

Kuwata

Tomita

et al. 1982

Microbiology and Immunology

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The effects of human a and fJ interferons (IFN) on the production of HBsAg by PLCjPRF/5 cells, an HBsAg-producing human hepatoma cell line, were studied in the exponential and stationary phases of cell growth. When exponential phase cells were treated with 100 or 1,000 U of IFN per ml for 48 hr, the amount of HBsAg in the culture medium decreased. The number of cells and the synthesis of DNA and proteins were also reduced by the IFN treatment. These results suggested that IFN did not affect the production of HBsAg specifically in exponential phase cells. When cells in the stationary phase were similarly treated with IFN, HBsAg production was not inhibited nor did the number of cells decrease.To examine the antiviral state induced by IFN in PLCjPRF/5, induction of 2'5'-0Iigo(A) synthetase and susceptibility to two kinds of viruses were examined. The 2'5'-0Iigo(A) synthetase activity was increased in an IFN-dose dependent manner. Susceptibility to vesicular stomatitis virus (VSV) and encephalomyocarditis virus (EMCV) was decreased by treatment with 10 and 100 U of IFN per ml for 20 hr. It was concluded that IFN-a and IFN-fJ induce 2'5'-0Iigo(A) synthetase and the antiviral state, but do not inhibit HBsAg production by PLC/ PRF/5 cells.Interferon (IFN) is known for its therapeutic effect in several human viral infections. Recently, a number of reports have suggested certain effects of IFN in the treatment of chronic hepatitis B virus infection (9,12,13,18). IFN treatment reduces hepatitis B virus-specific DNA-polymerase activity and other viral markers in the serum of patients with chronic hepatitis (22). Several viral markers also disappear or decrease in hepatic tissue (21). Other workers, however, observed no effect of IFN treatment except for a transient decrease in DNA-polymerase activity (26). These conflicting results may be attributed to the differences in the amount and duration of IFN treatment given or in the immunological state of the Abbreviations: IFN, interferon; VSV, vesicular stomatitis virus; EMCV, encephalomyocarditis virus; TCIDso, 50% tissue culture infectious dose; MEM, Eagle's minimal essential medium. 705

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“…Ara-A has been used in recent years in the treatment of chronic hepatitis B. It reduces, in a dose-dependent fashion, the serum levels of virus DNA-polymerase [34-381, with a loss of infectivity [39] and an overall improvement of liver disease [40] in some patients. However, ara-A also produces sideeffects, mostly gastrointestinal and neurological disturbances [41,42]; at doses higher than 25 mg.kg-'.day-', it also causes severe depression of bone marrow functions [43].…”

Section: Asialofetuin Conjugatesmentioning

confidence: 99%

Targeting of antiviral drugs by coupling with protein carriers

Fiume¹,

Busi²,

Mattioli³

1983

FEBS Letters

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Side effects of antiviral drugs might be circumvented by their selective delivery into infected cells. This targeting can be obtained by conjugation of the drugs to macromolecules which are taken up specifically by the infected cells. The experiments reviewed, on this approach to antiviral chemotherapy, are mainly directed at improving the chemotherapeutic index of adenine arabinoside (ara‐A) in the treatment of chronic hepatitis B by its coupling to galactosyl terminating glycoproteins.

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Antiviral treatment of chronic hepatitis B virus infection: Improvement in liver disease with interferon and adenine arabinoside

Cited by 94 publications

References 8 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

Effect of Interferon on the Production of HBsAg and Induction of an Antiviral State in Human Hepatoma Cell Line PLC/PRF/5

Targeting of antiviral drugs by coupling with protein carriers

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