Failure of acyclovir to enhance the antiviral effect of α lymphoblastoid interferon on HBe-seroconversion in chronic hepatitis B

Berk, Luuk; Schalm, Solko W.; Man, Robert A. de; Heytink, Rudolf A.; Berthelot, Pièrre; Bréchot, Christian; Boboc, B.; Degos, Françoise; Marcellin, Patrick; Benhamou, Jean‐Pierre; Heß, Georg; Rossol, S.; Büschenfelde, Karl‐Hermann Meyer zum; Chamuleau, R. A. F. M.; Jansen, Petér L. M.; Reesink, H. W.; Meyer, Beat; Beglinger, Christoph; Stalder, G; Ouden–Muller, Jannie W. den; Jong, M. de

doi:10.1016/0168-8278(92)90175-o

Cited by 41 publications

(8 citation statements)

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“…Ninety-seven HBeAg positive-CHB patients, who were included at our centre in IFN clinical trials between 1987 and 2000, were all retrospectively evaluated [17][18][19][20][21]. CHB was documented by the presence of HBsAg in serum for more than 6 months, and by liver biopsy showing histological features of chronic hepatitis compatible with HBV infection.…”

Section: Patient Populationmentioning

confidence: 99%

High rates of HBsAg seroconversion in HBeAg-positive chronic hepatitis B patients responding to interferon: A long-term follow-up study

Moucari¹,

Korevaar²,

Lada³

et al. 2009

Journal of Hepatology

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154

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Section: Patient Populationmentioning

confidence: 99%

High rates of HBsAg seroconversion in HBeAg-positive chronic hepatitis B patients responding to interferon: A long-term follow-up study

Moucari¹,

Korevaar²,

Lada³

et al. 2009

Journal of Hepatology

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170

154

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“…Nevertheless, ACV treatment of patients with HBV infection had no additional effect on serum HBeAg levels in patients also treated with alpha interferon (3). ACV given intravenously for 28 days had only a weak effect on viral replication and did not significantly increase the rate of seroconversion to anti-HBe in chronically infected patients (1).…”

mentioning

confidence: 99%

Antiviral Activities of Oral 1-O-Hexadecylpropanediol-3-Phosphoacyclovir and Acyclovir in Woodchucks with Chronic Woodchuck Hepatitis Virus Infection

Hostetler

Beadle

Hornbuckle

et al. 2000

Antimicrob Agents Chemother

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Acyclovir triphosphate is a potent inhibitor of hepatitis B virus DNA polymerase, but acyclovir treatment provides no benefit in patients with hepatitis B virus infection. This is due in part to the fact that hepatitis B virus, unlike herpes simplex virus, does not code for a viral thymidine kinase which catalyzes the initial phosphorylation of acyclovir. We synthesized 1-O-octadecyl-sn-glycero-3-phospho (3-P)-acyclovir and found that it was highly active in reducing hepatitis B virus replication in 2.2.15 cells, while acyclovir was inactive. The greater antiviral activity of 1-O-octadecyl-sn-glycero-3-P-acyclovir appeared to be due to liver cell metabolism of the compound to acyclovir monophosphate (K. Y. Hostetler et al., Biochem. Pharmacol. 53:1815-1822, 1997). However, a closely related compound without a hydroxyl group at the sn-2 position of glycerol, 1-Ohexadecylpropanediol-3-P-acyclovir, was more active and selective in 2.2.15 cells in vitro. In this study, we treated woodchucks chronically infected with woodchuck hepatitis virus with increasing oral doses of 1-Ohexadecylpropanediol-3-P-acyclovir and assessed the response to therapy versus acyclovir or a placebo. At a dosage of 10 mg/kg of body weight twice a day, the test compound significantly inhibited viral replication in vivo, as indicated by a 95% reduction in serum woodchuck hepatitis virus DNA levels and by a 54% reduction in levels of woodchuck hepatitis virus replicative intermediates in the liver. Higher doses were somewhat less effective. In contrast, 20 mg of acyclovir/kg twice daily, a 5.3-fold-higher molar dosage, had no demonstrable activity against woodchuck hepatitis virus. Oral 1-O-hexadecylpropanediol-3-P-acyclovir appeared to be safe and effective in chronic woodchuck hepatitis virus infection.Acyclovir [ACV; 9-(2-hydroxyethoxymethyl)guanine] is remarkably effective against herpes simplex virus (HSV) infection (7, 27). ACV is phosphorylated by an HSV-coded thymidine kinase (9) and is subsequently converted to ACV triphosphate by cellular enzymes (22). ACV triphosphate inhibits the DNA polymerase of HSV (6) and is incorporated into viral DNA, causing chain termination because ACV lacks the equivalent of a 3Ј-hydroxyl group.ACV triphosphate also inhibits the DNA polymerase of hepatitis B virus (HBV) and the DNA polymerase of woodchuck hepatitis virus (WHV) by 50% at 0.9 and 0.7 M, respectively (13). Nevertheless, ACV treatment of patients with HBV infection had no additional effect on serum HBeAg levels in patients also treated with alpha interferon (3). ACV given intravenously for 28 days had only a weak effect on viral replication and did not significantly increase the rate of seroconversion to anti-HBe in chronically infected patients (1). Zidovudine (AZT) triphosphate inhibits HBV DNA polymerase by 50% at 0.3 M (4), but AZT treatment had no effect on serum HBV DNA levels in AIDS patients with concomitant HBV infection (12,17). Poor phosphorylation of ACV has been noted previously in HepG2 cells (15) and in 2.2.15 cells (29). Thus, ...

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“…4,5 Many attempts to enhance this response rate have been unsuccessful. Treatment with nucleoside analogues, such as lamivudine, or combination of these agents with IFN-␣, does not yet appear to significantly increase the HBeAg seroconversion rate, [6][7][8] whereas the use of priming therapy with prednisone has not been generally accepted as a result of a lack of consistent results and the risk of hepatic decompensation. 4,9 How long we should treat chronic HBV patients with IFN-␣ is still not established.…”

mentioning

confidence: 99%

Interferon alfa for chronic hepatitis B infection: Increased efficacy of prolonged treatment

et al. 1999

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Interferon alfa (IFN-␣) is the primary treatment for chronic hepatitis B. The standard duration of IFN-␣ therapy is considered 16 weeks; however, the optimal treatment length is still poorly defined. We evaluated the efficacy and acceptability of prolonged IFN-␣ treatment in patients with chronic hepatitis B. To investigate whether treatment prolongation could enhance the rate of hepatitis B e antigen (HBeAg) seroconversion, we conducted a prospective, controlled, multicenter trial in which all patients were treated with a standard regimen of 10 million units IFN-␣ 3 times per week over 16 weeks. Patients who were still HBeAgpositive after 16 weeks of therapy were randomized to prolongation of the identical regimen up to 32 weeks (prolonged therapy) or discontinuation of treatment (standard therapy). Among the 162 patients who entered the study, 27 (17%) were HBeAg-negative after the first 16 weeks of treatment, and 118 were randomized to standard or prolonged therapy. After randomization, a response Worldwide, chronic hepatitis B virus (HBV) infection is a major cause of cirrhosis and hepatocellular carcinoma. Clearance of hepatitis B e antigen (HBeAg) indicates transition to a state of low-level viral replication that is accompanied by biochemical remission of liver disease and prolonged survival. 1-3 Interferon alfa (IFN-␣) has emerged as one of the most effective treatments for chronic hepatitis B, inducing HBeAg seroconversion in about one third of the patients. 4,5 Many attempts to enhance this response rate have been unsuccessful. Treatment with nucleoside analogues, such as lamivudine, or combination of these agents with IFN-␣, does not yet appear to significantly increase the HBeAg seroconversion rate, 6-8 whereas the use of priming therapy with prednisone has not been generally accepted as a result of a lack of consistent results and the risk of hepatic decompensation. 4,9 How long we should treat chronic HBV patients with IFN-␣ is still not established. The standard duration of treatment is considered 16 weeks. In several studies, IFN-␣ was given for a longer period, and some suggest additional benefit of prolonged therapy. 10,11 However, these studies contain a small number of patients, show considerable heterogeneity in patient population and response rates, and the results should therefore be interpreted with caution. In an uncontrolled pilot study, we successfully prolonged IFN-␣ treatment in those patients who approximated HBeAg seroconversion, as demonstrated by a continuous decrease of quantified serum HBV-DNA and HBeAg values, at the end of standard IFN-␣ therapy. 12 Therefore, we initiated a large, prospective, randomized, controlled trial investigating the efficacy of treatment prolongation with an additional 16 weeks in those patients who did not respond with HBeAg seroconversion during a standard 16-week IFN-␣ course. PATIENTS AND METHODSPatients. One hundred sixty-two patients from 16 European hepatologic centers (EUROHEP) 13 were enrolled after central evaluation of their eligibility. Th...

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Failure of acyclovir to enhance the antiviral effect of α lymphoblastoid interferon on HBe-seroconversion in chronic hepatitis B

Cited by 41 publications

References 8 publications

High rates of HBsAg seroconversion in HBeAg-positive chronic hepatitis B patients responding to interferon: A long-term follow-up study

High rates of HBsAg seroconversion in HBeAg-positive chronic hepatitis B patients responding to interferon: A long-term follow-up study

Antiviral Activities of Oral 1-O-Hexadecylpropanediol-3-Phosphoacyclovir and Acyclovir in Woodchucks with Chronic Woodchuck Hepatitis Virus Infection

Interferon alfa for chronic hepatitis B infection: Increased efficacy of prolonged treatment

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