Hepatitis B virus resistance to entecavir in nucleoside naïve patients: Does it exist?

Abstract

A ntiviral therapy of chronic hepatitis B remains a major clinical challenge. 1 On the one hand, the development of new antivirals has been shown to be efficacious in controlling viral replication, decreasing the inflammatory activity within the liver, and preventing the progression of chronic hepatitis toward its main complications including decompensation of liver cirrhosis and development of hepatocellular carcinoma. 2 On the other hand, due to the unique mechanism of viral replication and persistence of HBV in infected individuals, 3 longterm antiviral therapy is required in most individuals and thus places the patients at risk of selecting drug-resistant mutants and of developing progressive liver disease. 4 Therefore, new anti-HBV agents are needed in the armory for combating chronic hepatitis B and to design the best management strategies.The recent approval of entecavir in the United States and in Europe is providing, as a newcomer, new hope for the treatment of chronically infected patients with HBV. In clinical trials, entecavir administration for one year has shown a clear antiviral potency with more marked viral load suppression and a significant benefit in liver histology improvement as compared to lamivudine therapy. Its clinical efficacy was demonstrated in large numbers of patients enrolled in different phase III studies covering the most relevant clinical situations, including HBeAgpositive and -negative patients and lamivudine refractory patients. [5][6][7] These results allowed the approval of entecavir for the treatment of chronic hepatitis B by the FDA and EMEA. However, clinically relevant recommendations can only come from long-term evaluation. Thus, results from studies beyond one year of therapy are urgently needed. Indeed, one of the major problems faced by anti-HBV therapy is the slow kinetics of cccDNA clearance from the infected liver using nucleoside analogs either as monotherapy 3 or in combination with pegylated interferon-alpha. 8 One study performed in chronically infected woodchucks showed the effect of long-term entecavir treatment on cccDNA clearance without selection of drug-resistant mutants. 9 As a result of viral persistence, the subsequent selection of drug-resistant mutants from the viral quasi-species was considered inevitable with nucleoside analog monotherapy, as clearly shown by lamivudine and adefovir studies. The first cases of entecavir resistance were observed in patients receiving entecavir for lamivudine failure. 10 In this population of patients, genotypic resistance to entecavir was observed in 10 of 141 patients and virologic breakthrough in two patients after one year of therapy. 5 The resistance mutations were characterized genetically and phenotypically, and were shown to occur on a lamivudine-resistance mutation background. From these studies, a two hit model was suggested. The initial requirement for lamivudine resistance mutations was suggested by studies showing that these mutants have an approximately 10-fold reduced sensitivity to entecavir in vitr...

Current treatment of hepatitis B

“…These lesions include lung adenomas and carcinomas, and liver adenomas and carcinomas. The cumulative human risk will require post-marketing surveillance 116. As for all antiviral agents, resistance might be encountered in clinical practice in slow or incomplete responders, albeit a relatively low rate 117.…”

Tailoring antiviral therapy in chronic hepatitis B patients with lamivudine resistance

“…Furthermore, the selection rate of ETV resistant mutants is very low in naïve patients, but clinically relevant (9% at month 24) in patients with LMV resistance even if treated with higher ETV dose (1 mg vs 0.5 mg, [8]). Aminoacid substitutions within the YMDD motif of HBV polymerase that confer LMV resistance provide also the genetic background for ETV resistance, that occurs after additional substitutions at residues T184, S202 or M250 [11][12][13]. Accordingly, in 679 ETV naïve treated patient Colonno et al found that all viral breakthroughs with in vitro reduced susceptibility to ETV at week 96 were associated with baseline YMDD mutations [12].…”

“…Thus studies of viral dynamics characterizing early viral kinetics could estimate drug efficacy quickly [29,35] and allow earlier treatment optimizations by increasing ADV dose, as proposed by Hézode et al or changing drugs [9,15] according to response profiles mainly in highly viremic patients. Finally, the characterization of viral quasispecies at baseline before rescue therapy will become mandatory as soon as a wider spectrum of anti-HBV drugs will be available and we could make a further step towards a more personalized anti-HBV therapy as already available in HIV infected patients [2,13,36,37].…”

Virologic, serologic, and biochemical outcomes through 2 years of treatment with entecavir and lamivudine in nucleoside-naïve Chinese patients with chronic hepatitis B: a randomized, multicenter study

“…The emergence of resistant viral strains is an important consideration when selecting a nucleoside analogue. The very large pool of HBV in circulation, the rapid turnover rate, and the high error rate in HBV replication mean that any potential mutant, including those that give rise to drug resistance, may be present in a patient before he or she starts therapy [ 7 ]. The emergence of lamivudine resistance before and during therapy limits the usefulness of this drug.…”

“…Telbivudine selects for mutations in the YMDD motif and, although it is associated with lower resistance than lamivudine, recently reported virologic breakthrough due to resistance substitutions was 21.6% and 8.6% in HBeAg(+) and HBeAg(−) patients after 2 years of treatment [ 10 ]. The lowest reported rates of resistance after 5 years of treatment have been obtained with entecavir (<1%) [ 7 , 11 , 12 ].…”