Long-Term Efficacy of Tenofovir Monotherapy for Hepatitis B Virus-Monoinfected Patients After Failure of Nucleoside/Nucleotide Analogues

Abstract

Tenofovir disoproxil fumarate (TDF) has demonstrated high antiviral efficacy in treatment-naive patients with chronic hepatitis B virus (HBV) infection but experience in nucleoside/nucleotide analogue (NA)-experienced patients is limited. In this retrospective multicenter study we therefore assessed the long-term efficacy of TDF monotherapy in patients with prior failure or resistance to different NA treatments. Criteria for inclusion were HBV DNA levels >4.0 log 10 copies/mL at the start and a minimum period of TDF therapy for at least 6 months. In all, 131 patients (mean age 42 ؎ 12 years, 95 male, 65% hepatitis B e antigen [HBeAg]-positive) were eligible. Pretreatment consisted of either monotherapy with lamivudine (LAM; n ‫؍‬ 18), adefovir (ADV; n ‫؍‬ 8), and sequential LAM-ADV therapy (n ‫؍‬ 73), or add-on combination therapy with both drugs (n ‫؍‬ 29). Three patients had failed entecavir therapy. Resistance analysis in 113 of the 131 patients revealed genotypic LAM and ADV resistance in 62% and 19% of patients, respectively. The mean HBV DNA level at TDF baseline was 7.6 ؎ 1.5 log 10 copies/mL. The overall cumulative proportion of patients achieving HBV DNA levels <400 copies/mL was 79% after a mean treatment duration of 23 months (range, 6-60). Although LAM resistance did not influence the antiviral efficacy of TDF, the presence of ADV resistance impaired TDF efficacy (100% versus 52% probability of HBV DNA <400 copies/mL, respectively). However, virologic breakthrough was not observed in any of the patients during the entire observation period. Loss of HBeAg occurred in 24% of patients and HBsAg loss occurred in 3%. No significant adverse events were noticed during TDF monotherapy. Conclusion: TDF monotherapy induced a potent and long-lasting antiviral response in NA-experienced patients with previous treatment failure. Our data may have implications for current add-on strategies. (HEPATOLOGY 2010;51: 73-80.)A major limitation of nucleoside and nucleotide analogues (NA) in hepatitis B virus (HBV) therapy is the selection of HBV resistance variants, which can lead to a rebound in HBV replication and exacerbation of HBV-related disease. HBV polymerase gene variants that mediate HBV resistance are known to confer cross-resistance to other NAs. Today, increasing numbers of patients have experienced NA treatment failure, mostly to lamivudine (LAM) or adefovir dipivoxil (ADV), which poses a growing problem for antiviral treatment. Add-on combination therapy with ADV plus LAM was shown to be effective in these patients but only when initiated during the early stages of resistance development. 1 Tenofovir disoproxil fumarate (TDF) was licensed in 2008 for the treatment of HBV infections in Europe and the Abbreviations: ADV, adefovir dipivoxil; ALT, alanine aminotransferase; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; human immunodeficiency virus; LAM, lamivudine; NA, nucleoside/nucleotide analogue; PCR, polymerase chain reaction; TDF, tenofovir disoproxil fumarate. ...

No longer 'written off' – times have changed for the BBV-infected dental professional

“…64 As with any antiviral treatment that is taken in the long term, resistance is a concern, but tenofovir and entecavir have both so far demonstrated low rates of resistance. [65][66][67] The value of these drugs in supporting dentists who are chronic hepatitis B carriers and who wish to return to undertaking EPPs in dental practice is described later in this paper.…”

Treatment for hepatitis B in patients with drug resistance

“…In fact, TDF is less effective against mutant HBV strains containing the primary mutations associated with ADV resistance (rtA181T/V and/or rtN236T) in vitro (17). Patients with ADV-resistant HBV show an impaired response to TDF compared to patients without ADV resistance (22). More specifically, the rtA194T polymerase mutation has been found in HBV/HIV coinfected patients during TDF treatment, suggesting an association with TDF resistance (23).…”

“…There are some data from observational cohort studies suggesting that the efficacy of TDF is diminished in patients with ADV resistance (22,30). However, in a more recent randomized study comparing TDF or TDF + ETV in 102 patients with ADV-resistant chronic hepatitis B, both strategies were similarly effective (28).…”

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] .…”

“…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] . For patients who achieved insufficient effect by lamivudine and adefovir, tenofovir alone or with lamivudine achieved a 64% serum HBV DNA-negative conversion rate 96 wk after changing therapy [93] .…”