No detectable resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with chronic hepatitis B

Abstract

One major challenge in the treatment of chronic hepatitis B is to maintain long-term viral suppression without promoting the selection of drug-resistant mutations. We analyzed data from 347 hepatitis B e antigen-negative and 238 hepatitis B e antigenpositive patients receiving tenofovir disoproxil fumarate (TDF) in an open-label, longterm extension of two phase 3 studies. To date, resistance analyses have been completed for patients receiving up to 288 weeks (6 years) of TDF. Population sequencing of hepatitis B virus (HBV) polymerase/reverse transcriptase (pol/RT) was attempted for all patients at baseline, and any patient who remained viremic (HBV DNA 400 copies/ mL [69 IU/mL]) at week 288 or at the end of treatment with TDF (n 5 52) or emtricitabine (FTC)/TDF (n 5 7). Phenotypic analyses were performed in HepG2 cells using recombinant HBV containing patient pol/RT sequences. Approximately half of the patients on open-label treatment who qualified for genotyping had pol/RT sequence changes compared to baseline (23/52 [44%] on TDF, 4/7 [57%] on FTC/TDF). Most changes were at polymorphic sites and none were associated with TDF resistance. Virologic breakthrough occurred infrequently and was associated with nonadherence to study medication in the majority of cases (12/16, 75%). Per protocol, 57 patients (10%) were eligible to switch to FTC/TDF; the majority had HBV DNA <400 copies/mL at their last study visit regardless of whether they switched to FTC/TDF (n 5 34) or maintained TDF monotherapy (n 5 17). No patient exhibited persistent viremia (HBV DNA never <400 copies/mL) after week 240. Conclusion: TDF monotherapy maintains effective suppression of HBV DNA through 288 weeks of treatment with no evidence of TDF resistance. (HEPATOLOGY 2014;59:434-442) T he treatment goals for chronic hepatitis B (CHB)-infected patients are to improve quality of life and decrease the risk of life-threatening complications by potent and durable suppression of hepatitis B virus (HBV) replication. [1][2][3][4][5] As most patients with CHB will require long-term treatment with nucleos(t)ide analogs, one of the greatest challenges is to maintain effective viral suppression without the selection of resistance mutations. Long-term treatment with first-generation nucleos(t)ide analogs leads to relatively high cumulative resistance rates, 71% after up to 4 years of treatment with lamivudine (LAM), 6 and 29% in hepatitis B e antigen (HBeAg)-negative patients and 20% in HBeAg-positive patients after up to 5 years of treatment with adefovir (ADV). 7,8 Furthermore, 25% of HBeAg-positive patients and 11% of HBeAg-negative patients developed resistance after up to 2 years of treatment with telbivudine.9 Entecavir (ETV) has a markedly lower rate of resistance: 1.2% among treatment-na€ ıve patients treated for up to 5 years.10 However, ETV resistance develops rapidly in patients with prior resistance to LAM: the 5-year cumulative probability of developing ETV resistance is 51% in patients harboring LAM resistance.

Factors associated with HBV Virological Breakthrough

“…Subsequent studies have confirmed these findings by concurrently measuring virological breakthrough and non-adherence [18,20,[22][23][24], but none provided a consistent definition for non-adherence that is evidence-based. One of the most challenging issues in the field of medication adherence research is the use of varied definitions and arbitrary cut-off points to define adherence to therapies.…”

“…anti-viral therapies, recent reports have acknowledged the relationship between nonadherence and virological breakthrough [18,22,23,38]. provides key information to be delivered during patient education and adherence counselling.…”

“…There is growing clinical evidence [40,41] and clinician acknowledgement [19,42] [18,23,43]. Increasing clinician and patient awareness and improving education is imperative to achieve higher levels of adherent behaviour.…”

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“…ADV resistance rate is approximately 30% after a 5-year treatment, with even higher rates in NAs experienced patients (55). ETV and TDF are the drugs with a higher genetic barrier to resistance, reporting 1.2% of resistant mutation after 5 years of treatment for ETV, while no resistance has been previously been reported after 6 years of treatment for TDF (56,57).…”

Current and future directions for treating hepatitis B virus infection

“…A 5-year study showed that tenofovir achieved a higher HBsAg-negative conversion rate compared to other NUCs [91] . A recent report with 288 wk of follow up suggested that no apparent resistance mutations were observed [94] . For decompensated cirrhosis, the combination of tenofovir with emtricitabine was reported to achieve positive results [89] .…”