Tenofovir for patients with lamivudine-resistant hepatitis B virus (HBV) infection and high HBV DNA level during adefovir therapy

Abstract

Incomplete virological response to adefovir dipivoxil (ADV) has been observed in patients with lamivudine-resistant hepatitis B virus (HBV) infection and may be associated with developing resistance and disease progression. We therefore investigated whether the efficacy of viral suppression could be improved by replacing ADV with tenofovir disoproxil fumarate (TDF). Twenty patients with chronic HBV infection (18 HBeAg؉), viral breakthrough during lamivudine therapy, and persistent viral replication (>10 4 copies/mL) after 15 months of ADV monotherapy (range 4-28 months) were treated with TDF 300 mg daily and were retrospectively analyzed. A screening for nucleoside/nucleotide analogue resistance mutations within the HBV polymerase gene was performed in all patients by direct sequencing. Within a median of 3.5 months, application of TDF led to undetectable HBV DNA in 19 of 20 patients, as demonstrated by suppression of HBV DNA below the detection limit of 400 copies/mL. Initially elevated ALT levels had normalized in 10 of 14 patients by the end of follow-up (median 12 months, range 3-24 months). Four patients lost HBeAg, after 3, 4, 5, and 16 months, and one patient seroconverted to anti-HBs after 16 months of TDF therapy. Lamivudine-associated mutations (rtV173L, rtL180M, rtM204V/I) could be detected in 6 patients at baseline of TDF, but this obviously did not influence the response. ADV-resistant mutations were not detected. No side effects were reported. In conclusion, these preliminary observations strongly suggest that TDF might be a highly effective rescue drug for HBV-infected patients with altered responsiveness to treatment with lamivudine and ADV. (HEPATOLOGY 2006;44:318-325.) See Editorial on Page 309 C omplete and sustained suppression of viral replication remains the most important goal in the treatment of patients with chronic hepatitis B virus (HBV) infection. 1,2 In this respect, the introduction of the nucleoside analogue lamivudine and the nucleotide analogue adefovir dipivoxil (ADV) largely improved the outcome in these patients, also by preventing hepatitic decompensation or the development of hepatocellular carcinoma. [3][4][5] These compounds also have a place when interferon-alpha based therapy is contraindicated, as in patients with acute liver failure, decompensated cirrhosis, or extrahepatic manifestations.However, a major disadvantage of nucleoside/nucleotide analogues is that resistant hepatitis B virus mutants develop during long-term treatment, limiting the efficacy of these analogues in suppressing viral replication. As demonstrated in recent studies, approximately 70% of patients receiving lamivudine therapy for more than 4 years suffer the emergence of lamivudine-resistant HBV Abbreviations: ADV, adefovir dipivoxil; HBV, hepatitis B virus; TDF, tenofovir disoproxil fumarate; HBeAg, hepatitis B virus e antigen. From the

Tenofovir (TDF) has stronger antiviral effect than adefovir (ADV) against lamivudine (LAM)-resistant hepatitis B virus (HBV)

“…TDF + LAM group was superior to other groups (Table 3). Van Bommel et al [13] not only found the higher potency of TDF over ADV in treatment naive patients with hepatitis B, but also among patients with LAM resistance who showed incomplete response to ADV in patients [20]. Furthermore, Del Poggio et al [21] found that low-dose TDF (75 mg) was more potent than adefovir (10 mg) in chronic HBeAg-negative hepatitis B.…”

Current and future directions for treating hepatitis B virus infection

“…With tenofovir treatment, the serum HBV DNA-negative conversion rate for patients without adefovir-resistance was 100%, but the rate was down to 52% for patients with adefovir-resistance [89] . An important feature of tenofovir is that tenofovir alone or with emtricitabine exerts an anti-viral effect to lamivudine, adefovir or entecavir resistance mutants [85,86,93,95,96] . For example, an article reported that for patients who achieved an insufficient effect by lamivudine, adefovir or the combination of these two drugs, tenofovir resulted in a serum HBV DNA-negative conversion rate of 79%, HBeAg-negative conversion rate of 24% and HBsAg-negative conversion rate of 3% of all patients (the median time from administration to HBsAg-negative conversion was 23 mo) [86] .…”

Recent data on treatment of chronic hepatitis B with nucleos(t)ide analogues

“…Increased dosage to 20 mg daily with careful monitoring of renal function achieved better efficacy and can be considered in patients with elevated ALT levels, severe, or rapidly progressive liver disease [80].…”

“…Before the availability of adefovir in some region, tenofovir has been used successfully for lamivudine resistance [132]. Subsequent switch back to adefovir resulted in viral relapse in 60% of patients.…”