Health & Medical hepatitis

Switching Patients With Lamivudine Resistant Chronic HBV

Switching Patients With Lamivudine Resistant Chronic HBV
The nucleotide analogues, tenofovir disoproxil fumarate and adefovir dipivoxil, inhibit viral replication and are both effective against the hepatitis B virus (HBV). In our department, tenofovir was prescribed in addition to lamivudine for the treatment of lamivudine resistant chronic hepatitis B. After registration of adefovir, 10 patients were switched to adefovir monotherapy. We studied changes in HBV-DNA and alanine aminotransferase (ALT) in these patients. The median treatment duration with tenofovir was 78 weeks resulting in a median viral load reduction of 5.4 (range 6.8–2.3) log10 copies/mL compared to baseline (P = 0.005). Two patients had an increase >1 log10 copies/mL during tenofovir treatment. After the switch to adefovir, six out of 10 patients had an HBV-DNA >4 log10 copies/mL and the median HBV-DNA increased from 2.8 to 4.5 log10 copies/mL (P = 0.017). The factors associated with relapse were HBV-DNA PCR positivity at the time of switch and genotype B or D. ALT levels at the beginning of tenofovir treatment also might be a factor. Retreatment with tenofovir (n = 3) resulted in a rapid decline in HBV-DNA. Tenofovir is a potent antiviral drug. Switching to adefovir resulted in viral relapse in 60% of patients and retreatment with tenofovir resulted again in viral decline, which suggests that tenofovir is a more potent antiviral agent.

Although 350–400 million people worldwide are infected with hepatitis B, to this date, treatment is frequently unsuccessful. Interferon-α (IFN) treatment or pegylated IFN-α (PEG-IFN) results in a sustained response in 30–40% of treated patients. Many rely on long-term viral suppression with nucleoside or nucleotide analogues to prevent disease progression. Nucleosides or nucleotides act by inhibiting the viral polymerase, thereby suppressing the viral replication of HBV and improving serum transaminase levels and liver histology. In hepatitis Be antigen (HBeAg)-positive patients, the loss of HBeAg is enhanced. The long-term treatment may select for mutations within the viral polymerase that promote antiviral resistance resulting in an increase in liver inflammation and worsening of liver histology. Lamivudine has a high resistance rate of 15–30% after 1 year of treatment, which increases to 60–70% after continuous treatment.

The nucleotides, tenofovir disoproxil fumarate (DF) and adefovir dipivoxil, exhibit both activity against wild-type virus and lamivudine resistant mutants in vitro and in vivo. Tenofovir disopoproxil fumarate is an oral prodrug of tenofovir, a nucleotide (nucleoside monophosphate) analogue with activity against retroviruses, including HIV-1, HIV-2 and hepadnaviruses. Following absorption, tenofovir DF is rapidly converted to tenofovir, which is metabolized intracellularly to the active tenofovir diphosphate. The active form of tenofovir is a competitive inhibitor of HBV transcriptase and terminates the growing DNA chain.

Several small studies suggest a more potent antiviral effect of tenofovir compared to adefovir. It is not known whether viral suppression is maintained after switching to adefovir or whether it is effective in case of viral breakthrough on tenofovir treatment, however, several cases suggest the loss of efficacy in some patients. In our Department, tenofovir was added to lamivudine to combat viral breakthrough due to lamivudine resistance during a period in which adefovir was not yet available. After adefovir dipivoxil became available as a registered product and the tenofovir containing regimen was switched to adefovir monotherapy. Its availability enabled us to study the ability of adefovir treatment to sustain tenofovir-induced disease remission.

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