Virological breakthrough and resistance in patients with chronic hepatitis B receiving nucleos(t)ide analogues in clinical practice
慢性乙肝核苷药物治疗中的DNA反弹与病毒变异
肝胆速递：DNA反弹并非都与变异有关；规律检测DNA水平很重要
Virological breakthrough and resistance in patients with chronic hepatitis B receiving nucleos(t)ide analogues in clinical practice†
Chanunta Hongthanakorn,
Watcharasak Chotiyaputta,
Kelly Oberhelman,
Robert J. Fontana,
Jorge A. Marrero,
Tracy Licari,
Anna S. F. Lok‡,*
Hepatology
Article first published online: 25 MAY 2011
DOI: 10.1002/hep.24318
Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI
*Division of Gastroenterology, University of Michigan Health System, 3912 Taubman Center, SPC 5362, 1500 East Medical Center Drive, Ann Arbor, MI 48109
†
Potential conflict of interest: R.J.F. did consulting/research for Bristol-Myers Squibb and GlaxoSmithKline, and was on the Speaker's Bureau for Gilead Sciences and Genentech. A.S.F.L. did consulting for Gilead Sciences, Roche, Bristol-Myers Squibb, and GlaxoSmithKline; and received grant/research support from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Schering-Plough, and Roche.
Virological breakthrough (VBT) is the first manifestation of antiviral drug resistance during nucleos(t)ide analogue (NUC) treatment of chronic hepatitis B (CHB), but not all VBTs are due to drug resistance. This study sought to determine the incidence of VBT and genotypic resistance (GR) in patients with CHB who were receiving NUCs in clinical practice. Records of patients with CHB who were receiving NUCs were reviewed. All patients with VBT were tested for drug resistance mutations. Of 148 patients included, 73% were men and mean age was 44.9 years. During a mean follow-up of 37.5 ± 20.1 months, 39 (26%) patients had at least 1 VBT. Of these 39 patients, 15 (38%) were not confirmed to have VBT on retesting, and 10 of these 15 had no evidence of GR. The cumulative probability of VBT, confirmed VBT, and GR at 5 years was 46.1%, 29.7%, and 33.9%, respectively. In multivariate analysis, failure to achieve undetectable hepatitis B virus (HBV) DNA was the only factor significantly associated with VBT. Among the 10 patients who had VBT but no confirmed VBT or GR and who were maintained on the same medications, serum HBV DNA decreased in all 10, and nine had undetectable HBV DNA at a mean of 6.8 months after the VBT. Four patients had persistently undetectable HBV DNA, six had transient increase in HBV DNA during follow-up, and none had GR. Conclusion: VBT was common in patients with CHB receiving NUCs in clinical practice, but nearly 40% of the VBTs were not related to antiviral drug resistance. Counseling of patients with CHB on medication adherence and confirmation of VBT and/or GR can avoid unnecessary changes in antiviral medications. (HEPATOLOGY 2011;)
Five nucleos(t)ide analogues (NUCs)—lamivudine, adefovir, entecavir, telbivudine, and tenofovir—have been approved for the treatment of chronic hepatitis B (CHB). NUCs are administered orally and have very few side effects; however, these medications suppress but do not eradicate hepatitis B virus (HBV). Therefore, most patients with CHB will require long-term treatment to derive clinical benefit. However, long-term NUC treatment is associated with increasing risk of drug resistance, particularly when NUCs with low genetic barrier to resistance are used as monotherapies.
Virological breakthrough (VBT) is the first clinical manifestation of antiviral drug resistance and may precede biochemical breakthrough (BBT).1-3 Phase 3 clinical trials of NUCs in NUC-naive patients revealed that 0%-87.5% of patients with VBT had confirmed genotypic resistance (GR).4-9 In the phase 3 trial of telbivudine versus lamivudine, 32 of 680 (4.7%) and 99 of 687 (14.4%) patients who received telbivudine and lamivudine, respectively, experienced VBT after 1 year of treatment, but only 28 (87.5%) and 75 (75.8%) patients with VBT were confirmed to have GR.9 In the phase 3 trial of entecavir versus lamivudine, 11 of 679 (1.6%) and 88 of 668 (13.2%) patients who received entecavir and lamivudine, respectively, experienced VBT after 1 year of treatment, but 0 (0%) of the entecavir-treated and 65 (73.9%) of lamivudine-treated patients with VBT were confirmed to have GR.7, 8 In the phase 3 trial of tenofovir, 10 of 426 (2.3%) patients who received tenofovir experienced VBT after 1 year of treatment, but none of these patients were confirmed to have GR.4 These data indicate that not all VBTs are related to antiviral drug resistance.
Possible explanations for the discrepancy between the rates of VBT and GR include poor adherence to medications, failure to detect drug-resistance mutations due to insensitive assays, and failure to recognize new mutations associated with antiviral drug resistance. VBT during the first year of treatment was attributed to medication nonadherence in patients who received entecavir or tenofovir in the phase 3 trials.4, 7 Medication adherence is likely to be lower in clinical practice than in phase 3 clinical trials, where highly motivated patients are recruited and closely monitored. Differentiating between VBT due to medication nonadherence and VBT due to drug resistance is important, because virological response can be restored by reinforcement of adherence in the former case whereas rescue therapy is needed in the latter situation.
The aims of this study were (1) to determine the incidence of VBT and GR in patients with CHB who were treated with NUCs in clinical practice, (2) to determine the factors associated with VBT in patients with CHB who were receiving NUCs, and (3) to determine the outcomes of patients with VBTs that were not confirmed to be associated with antiviral drug resistance mutations.
ALT, alanine aminotransferase; Anti-HBe, antibody to hepatitis B e antigen; BBT, biochemical breakthrough; CHB, chronic hepatitis B; CI, confidence interval; GR, genotypic resistance; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HIV, human immunodeficiency virus; HR, hazard ratio; NUC, nucleos(t)ide analogue; ULN, upper limit of normal; VBT, virological breakthrough.
This study examined the rates of VBT, confirmed VBT and GR in 148 CHB patients treated with NUCs in clinical practice. We found a high rate of VBT, 39 (26%) patients experienced at least 1 episode of VBT with a cumulative probability of 46% at 5 years. Twenty-four (16%) patients had confirmed VBT; of these, 19 (79%) had GR by direct sequencing. An additional five patients had GR but were not confirmed to have VBT on retesting or received rescue therapy without retesting. Thus, in total 24 (16%) patients had GR. The finding that 38% of patients who experienced VBT were not confirmed to have VBT on retesting and 38% did not have antiviral resistance mutations on direct sequencing suggests that medication nonadherence may be the cause of the VBT in these patients.
We acknowledge that direct sequencing is insensitive and will not detect viral variants that comprise <20% of the viral population. In this study, all patients were also tested by a line probe assay which is more sensitive and can detect viral variants that comprise >5% of the viral population. Two additional patients were found to have N236T mutation by the line probe assay. Thus, signature antiviral resistance mutations were not detected in 13 (33%) patients with VBT by both direct sequencing and line probe assay. None of these 13 patients was noted to have other substitutions in the reverse transcriptase region of the HBV polymerase gene. Only one had BBT. In phase 3 clinical trials of NUCs for CHB, 65.7% to 87.5% of patients receiving lamivudine or telbivudine and 0% of patients receiving entecavir or tenofovir, who experienced VBT during the first year had GR.4, 7-9
Although antiviral resistance mutations may be detected if we had used more sensitive methods such as single genome sequencing or pyrosequencing, follow-up data suggest that most of the patients who experienced VBT but did not have confirmed VBT or GR were not adherent to their antiviral medication(s). Because this was a retrospective study, data on medication adherence was not available; however, follow-up data suggest that non adherence was an important cause of these unconfirmed VBTs. All 10 patients who continued treatment with the same medication(s) had further decrease in serum HBV DNA levels and all but one had undetectable HBV DNA after the VBT. Six of these 10 patients experienced ≥1 episode of transient increase in serum HBV DNA level during follow-up despite counseling on the importance of medication adherence. None of the five retested for GR was found to have antiviral resistance mutations and all had subsequent decline in serum HBV DNA during continued treatment with the same medication(s). We acknowledge that our attribution that nonadherence was an important cause of VBT is speculative. In a separate prospective study of 105 patients in whom adherence was evaluated using a self-administered questionnaire, 26% admitted to missing their medication at least once in the past 30 days and patients who had <100% adherence on serial assessments had a trend toward a higher rate of VBT.14 Medication adherence has been shown to be important in maintaining response in patients receiving treatment for other conditions. Published studies showed that patients who were adherent to antihypertensive medications were more likely to have adequately controlled blood pressure.15-17 Several studies of antiretroviral medications in patients with HIV infection also revealed that failure to adhere to HIV treatment regimens and repeated drug holidays (defined as stopping treatment entirely for ≥48 hours) were associated with a higher rate of virological failure.18, 19 In one study of HIV treatment that included a protease inhibitor, 80% of patients with <80% adherence had virological failure, compared to 22% of those with ≥95% adherence.20
There are very little data on adherence to NUC treatment for hepatitis B. In a previous study of a pharmacy claims database that included 11,100 patients receiving NUCs for CHB, we found that mean adherence 1 year after enrollment, defined as percent of days in which the patient had medications during that year, was 87.8%.21 In that study, we were not able to correlate medication adherence with virological response or occurrence of VBT. In the current study, we found that nadir response and type of medication used were significantly associated with the occurrence of VBT. Thus, patients who had rapid response with undetectable serum HBV DNA within 1 year of treatment and those who had undetectable serum HBV DNA at some point during the course of treatment were less likely to experience VBT. These data are in accord with previous studies showing that undetectable serum HBV DNA after 24 weeks of treatment is associated with significantly lower rates of antiviral resistance.22, 23 As expected, among NUC-naive patients, those receiving entecavir monotherapy were less likely to experience VBT than those receiving lamivudine monotherapy. Among NUC-experienced patients, those receiving combination therapy (lamivudine + adefovir or emtricitabine + tenofovir) or tenofovir monotherapy were less likely to experience VBT than those receiving lamivudine, adefovir, or entecavir monotherapy. This is not surprising, because these patients had previous nonresponse or resistance to lamivudine or adefovir, and it is now known that switching from lamivudine to adefovir or entecavir monotherapy in patients with prior lamivudine resistance is associated with a high rate of subsequent resistance to adefovir or entecavir.24-26 In this study, all the patients who received entecavir or tenofovir alone or in combination with another NUC had undetectable HBV DNA within 6 months of rescue therapy, whereas three patients with lamivudine resistance still had detectable HBV DNA 6 months after rescue therapy with adefovir alone or in combination with lamivudine.
In conclusion, this study revealed that VBT was common in clinical practice. However, VBT was not always related to antiviral drug resistance. Patients with CHB receiving NUC therapy who experienced VBT should be counseled on medication adherence, and for patients who are immunocompetent and have compensated liver disease, confirmation of VBT and/or determination of GR is prudent before the initiation of rescue therapy to avoid unnecessary changes in antiviral medications. We acknowledge that this study is limited by the small number of patients, the heterogeneity in treatment regimens, and the lack of data on medication adherence. However, the results of this study highlight the importance of HBV DNA monitoring and counseling on medication adherence throughout the course of NUC treatment and the fine balance between prompt initiation of rescue therapy versus avoidance of unnecessary changes to the treatment regimen. 作者: 肝胆速递 时间: 2012-8-25 16:31
