Reactivation of viral replication after replacement of tenofovir by adefovir

Bömmel, Florian van; Berg, Thomas

doi:10.1002/hep.20765

Cited by 17 publications

(13 citation statements)

References 10 publications

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“…It is also likely that a 75 mg dose of TDF is more potent than 10 mg of adefovir, and in fact 3 out of 7 patients had a persistent viral rebound when shifted from TDF to adefovir. This is in agreement with the findings of Van Bommel and Berg [13] who observed a reactivation of viral replication after replacement of TDF 300 mg with adefovir 10 mg. Despite being equipotent in vitro, adefovir is thus much less potent in vivo than TDF and can not retain the TDF response, whether it has been achieved with a 300 mg or with a 75 mg dose of TDF.…”

Section: Discussionsupporting

confidence: 93%

Low-dose tenofovir is more potent than adefovir and is effective in controlling HBV viremia in chronic HBeAg-negative hepatitis B

Poggio¹

2007

WJG

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AIM:To study the efficacy of tenofovir disoproxil fumarate (TDF) at low dose in a small open trial of chronic hepatitis B patients with advanced stage disease. METHODS:Eleven patients were treated with TDF 75 mg for a median period of 80 (range, 24-576) wk and then 7 cases were shifted to an adefovir 10 mg treatment group. All patients had been pre-treated with lamivudine: 5 had YMDD resistant mutants and 6 wildtype virus. When TDF was started, 4 patients had lowlevel viremia and 6 were PCR-negative. RESULTS:During TDF treatment, PCR remained negative in 10 patients, transaminase levels were normal and no significant viral breakthrough was observed. The drug was well tolerated in all cases. When TDF 75 mg was substituted with adefovir 10 mg, 3 out of 7 patients had a persistent viral rebound (2700-130 000 copies/mL), in whom lamivudine had to be reintroduced. CONCLUSION:Low-dose TDF monotherapy can control HBV viremia for an extended period of time without the emergence of resistance and is more potent than adefovir at the standard dosage. The use of a reduced dose of TDF could diminish the cost of therapy in low-income countries, but further studies in a larger population and in HBeAg-positive subjects are needed.

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Section: Discussionsupporting

confidence: 93%

Low-dose tenofovir is more potent than adefovir and is effective in controlling HBV viremia in chronic HBeAg-negative hepatitis B

Poggio¹

2007

WJG

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“…Tenofovir and adefovir have similar anti-HBV activity in vitro [13]; however, whereas a standard dose of ADV is 10 mg, a standard dose of TDF is 300 mg, which represents a 30-fold increase in drug. Data from other studies have demonstrated that 300 mg of TDF has greater antiviral activity than does 10 mg of ADV [14] and that in patients with HBV in whom TDF is replaced by ADV, the levels of HBV DNA in the serum increase [15]. In the remaining 2 patients, the observed effect of treatment with ADV was based on 1 unconfirmed determination of HBV DNA.…”

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confidence: 97%

Hepatitis B Virus Containing the I233V Mutation in the Polymerase Reverse‐Transcriptase Domain Remains Sensitive to Inhibition by Adefovir

Curtis¹,

Zhu²,

Borroto–Esoda³

2007

J INFECT DIS

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An isoleucine-to-valine change at position 233 (rtI233V) of hepatitis B virus (HBV) polymerase was recently reported to cause decreased in vitro susceptibility to, and treatment failure of, adefovir dipivoxil (ADV). To further evaluate these findings, we screened our ADV clinical-study sequence database of 853 patients and identified 4 who, at baseline, had HBV with this mutation. All 4 patients responded to treatment with ADV, with a median change in HBV DNA levels of 4.0 log 10 copies/mL after 48 weeks of treatment. Phenotypic evaluation of clinical isolates and of a laboratory strain with the rtI233V mutation demonstrated their full susceptibility to adefovir in vitro, and HBV with the rtI233V mutation developed in none of the patients.Adefovir dipivoxil (ADV) is a nucleotide analogue that is used for the treatment of patients with chronic hepatitis B, including patients infected with HBeAg ϩ or HBeAg Ϫ types of hepatitis B virus (HBV), lamivudine-resistant HBV, liver transplant, and HIV coinfection [1]. On the basis of results on ‫0001ف‬ patients enrolled in clinical studies of ADV, 2 mutations associated with resistance to adefovir were identified in the polymerase region of HBV: rtN236T and rtA181V [2]. These 2 mutations were demonstrated to have a strong correlation with clinical-treatment failure and to confer a statistically significant reduction of drug susceptibility in vitro [3]. The cumulative probability of mutations associated with resistance to adefovir is 0%, 3%, 11%, 18%, and 29% after 1, 2, 3, 4, and 5 years, respectively [4]. An isoleucine-to-valine change at position 233 (rtI233V) of HBV polymerase was recently reported to cause both primary resistance to ADV in 3 patients, as evidenced by a lack of suppression of HBV DNA levels on initiation of treatment with ADV, and a decrease in susceptibility to adefovir in vitro [1]. The aim of the present study was to evaluate the incidence of the rtI233V mutation and to evaluate its impact on treatment with ADV in a large cohort of patients enrolled in clinical studies of ADV. Patient and methods. Patients from 4 clinical studies of ADV were included in this evaluation: studies GS-98-437 and GS-98-438 were placebo-controlled phase 3 randomized trials designed to evaluate the efficacy of 10 mg of ADV over a 96-week period, in patients with HBeAg ϩ and HBeAg Ϫ chronic hepatitis B [5, 6], respectively; study GS-98-435 was an open-label phase 3 compassionate-use study designed to evaluate the safety and efficacy of 10 mg treatment with ADV in patients with lamivudineresistant chronic hepatitis B either before or after liver transplantation [7]; and study GS-98-412 (extension phase) was a phase 2 dose range-finding study of ADV. All studies were approved by local Investigational Review Boards, and all of the patients in these studies provided written informed consent. Levels of HBV DNA in the serum were determined by the Roche Amplicor polymerase chain reaction (PCR) assay, with 1000 copies/mL as the lower limit of quantitation. Genotypic analysis of the ...

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“…In adefovir treatment failures the more potent drug tenofovir showed good viral suppression [93] . Patients responding to tenofovir and switched to adefovir showed viral relapse, while no mutants could be detected [94] . Another strategy could be adding a second drug to the failing compound.…”

Section: Management Of Treatment Failures To Nucleos(t)ide Analoguesmentioning

confidence: 95%

Future prospectives for the management of chronic hepatitis B

Leemans

Janssen

Man³

2007

WJG

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Chronic hepatitis B virus infection affects about 400 million people around the globe and causes approximately one million deaths a year. Since the discovery of interferon-α as a therapeutic option the treatment of hepatitis B has evolved fast and management has become increasingly complicated. T h e a m o u n t o f v ira l re p l ic a t io n re f le c t e d in t he viral load (HBV-DNA) plays an important role in the development of cirrhosis and hepatocellular carcinoma. The current treatment modalities for chronic hepatitis B are immunomodulatory (interferons) and antiviral suppressants (nucleoside and nucleotide analogues) all with their own advantages and limitations. An overview of the treatment efficacy for both immunomodulatory as antiviral compounds is provided in order to provide the clinician insight into the factors influencing treatment outcome. With nucleoside or nucleotide analogues suppression of viral replication by 5-7 log10 is feasible, but not all patients respond to therapy. Known factors influencing treatment outcome are viral load, ALT levels and compliance. Many other factors which might influence treatment are scarcely investigated. Identifying the factors associated with response might result in stopping rules, so treatment could be adapted in an early stage to provide adequate treatment and avoid the development of resistance. The efficacy of compounds for the treatment of mutant virus and the crossresistance is largely unknown. However, genotypic and phenotypic testing as well as small clinical trials provided some data on efficacy in this population. Discontinuation of nucleoside or nucleotide analogues frequently results in viral relapse; however, some patients have a sustained response. Data on the risk factors for relapse are necessary in order to determine when treatment can be discontinued safely. In conclusion: chronic hepatitis B has become a treatable disease; however, much research is needed to tailor therapy to an individual patient, to predict the sustainability of response and determine the best treatment for those failing treatment.

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Reactivation of viral replication after replacement of tenofovir by adefovir

Cited by 17 publications

References 10 publications

Low-dose tenofovir is more potent than adefovir and is effective in controlling HBV viremia in chronic HBeAg-negative hepatitis B

Low-dose tenofovir is more potent than adefovir and is effective in controlling HBV viremia in chronic HBeAg-negative hepatitis B

Hepatitis B Virus Containing the I233V Mutation in the Polymerase Reverse‐Transcriptase Domain Remains Sensitive to Inhibition by Adefovir

Future prospectives for the management of chronic hepatitis B

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