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Discussion This retrospective analysis, which thus far is the largest clinical experience of suboptimal responders to ETV, demonstrates excellent treatment response and tolerability to TDF monotherapy in chronic hepatitis B patients with prior suboptimal response to ETV. Entecavir is a potent inhibitor of HBV replication, and the suboptimal virological response is rarely seen in clinical practice. The suboptimal response rate of 2.9% in our study is quite low, particularly when compared with those of other antiviral agents with lower potency such as adefovir (approximately 30%),[url=][20][/url] lamivudine (13%)[url=][3][/url] and telbivudine (5%).[url=][3][/url]
The major concern for patients with suboptimal response to oral antiviral therapy is the issue of adequate therapeutic levels. In healthy subjects, ETV is rapidly absorbed, with the peak plasma concentration occurring within 1-h postdosing and with an effective half-life of approximately 24 h. The absorption of ETV has been shown to be altered significantly with food intake, as noted by a decrease in approximately 20% area under the curve serum concentration.[url=][21,22][/url] As a result, ETV is recommended to be taken on an empty stomach. In a recent analysis of 11 100 patients in the United States, the adherence rate to nucleos(t)ide analogues was reported to be higher than 85% among adults with chronic hepatitis B.[url=][23][/url] In this study, we devotedly instructed all the patients to take ETV regularly and on an empty stomach. Patient adherence to ETV was assessed by pill-count in 10 patients and by self-reporting in four patients; however, we recognize that these methods may have had limitations in being ideal to confirm treatment adherence. Yet, a few patients had suboptimal response, which was defined as a failure to achieve HBV-DNA reduction of more than 1 log10 over a 24-week period after a plateau in response was noted after initiation of ETV therapy. The median HBV-DNA reduction from baseline in patients in our study was approximately 4 log10 copies/mL, but after reaching an ongoing nonresponse state, the median decline was 0.43 (−0.09–1.13) log10 copies/mL. This difference in initial response was less than the antiviral effect seen in the ETV registration trials, which was approximately 7 log10 copies/mL reduction in HBeAg-positive patients and 5 log10 copies/mL reduction in HBeAg-negative patients at 24 weeks.[url=][10,24][/url] Thus, the relatively slow decline in HBV-DNA level during the first 24 weeks may be an early sign of suboptimal response.
The mechanism of suboptimal response to oral antiviral therapy is unclear. It may be related to either host (e.g., genetic polymorphisms involved in drug metabolism) or viral factors (e.g., preexisting mutations in HBV polymerase gene). In vitro studies and clinical evidence have indicated that there is a high genetic barrier to the development of resistance with ETV therapy, whereby multi-steps of mutations are required.[url=][16,25][/url] The presence of preexisting ETV-resistant HBV strain is very unlikely, particularly in those who were never exposed to nucleos(t)ide analogues.[url=][10][/url] However, in those nucleos(t)ide-experienced-patients, this barriers seem to be partially broken down. Baldick et al. [url=][26][/url] demonstrated that ETV susceptibility decreased approximately eightfold with the presence of lamivudine resistance substitutions (i.e., M204V and L180M) in HBV reverse transcriptase, and it has longitudinally been correlated with both genotypic resistance and increased circulatory HBV-DNA. Notably, ETV at 0.5-mg daily dosing appears to be suboptimal in lamivudine refractory,[url=][27][/url] and even with a higher dose (1 mg daily), a significant proportion (more than 16%) of patients still developed viral breakthrough with long-term treatment.[url=][12][/url] Taken together, it is possible that a proportion of our patients had exposure to lamivudine, or other compounds and had not informed the treating Physicians, or had baseline-resistant variants which could potentially have induced HBV mutations affecting ETV susceptibility. A limitation of our experience is that a population-based sequence HBV genotypic resistance assay was used, and it has a detectability threshold of 20–25%. A more sensitive assay such as a clonal based sequencing assay (Inno-Lipa, Innogenetics Inc., Gent, Belgium), which has a 5% threshold for resistant population, was not used.[url=][18][/url] Therefore, it is possible that some of our patients had preexisting lamivudine and/or ETV-resistant variations and thus the reason for suboptimal response to ETV therapy. In fact, recent studies from Canada and China have reported on the prevalence of preexisting HBV antiviral resistance mutations among treatment-naïve patients when tested with a highly sensitive resistance assay. Mutations associated with the L180/M240 pathway were relatively common (3–13%), whereas those associated with the A180 or N236 pathway were rare (0–0.6%).[url=][28,29][/url] Interestingly, preexisting ETV-related resistant variants (S202 and M250) were reported in up to 5% of treatment-naïve patients.[url=][28][/url]
In the present study, TDF monotherapy was shown to be very effective in patients with suboptimal response to ETV. Ten patients (71.4%) had undetectable HBV-DNA at week 24 after TDF treatment, and eventually all patients achieved undetectable HBV-DNA with a median duration of 30 weeks. Two of seven (29%) HBeAg-positive patients following TDF for at least 48 weeks also achieved HBe seroconversion. These response rates are nearly similar to treatment responses in HBeAg-positive treatment-naïve patients in Phase III study of TDF.[url=][30][/url]
Tenofovir, a nucleotide analogue, is structurally different from ETV or lamivudine and shares no cross-resistance.[url=][18][/url] In vitro studies have shown that HBV mutations associated with lamivudine resistance (M204V and/or L180M) and ETV resistance (M204V + L180M + S202G) remain fully sensitive to TDF. Clinical reports have demonstrated TDF to be an effective long-term therapeutic agent for patients after failure of lamivudine and adefovir.[url=][13–15][/url] There are isolated cases wherein TDF efficacy in ETV failure or resistance has been reported.[url=][13,19][/url] Thus, to our knowledge, our experience represents the largest with the effective use of TDF in patients with suboptimal response to ETV. The current American Association of the Study of the Liver Disease and the European Association of the Study of the Liver guidelines have suggested a switch to TDF or adding TDF in patients with resistance or suboptimal response to ETV presumably based on in vitro data. Our experience should serve to support this recommendation although we prefer switching to TDF monotherapy rather than adding TDF to ETV owing to an excellent efficacy of TDF monotherapy demonstrated in our patients as well as the lack of long-term safety data of TDF and ETV in combination.
A recent multicentre European study has demonstrated that the majority of patients with partial virological response to ETV (defined by more than 1 log10 decline, but failure to achieve undetectable HBV-DNA after 48 weeks of ETV therapy) can be successfully managed by further continuing ETV.[url=][31][/url] In this study, 29/36 patients (81%), from a total of 243 nucleos(t)ide-naïve and 90 patients nucleos(t)ide-experienced patients who received ETV, who had partial virological response to ETV, achieved HBV-DNA negativity after 15 additional months of ETV therapy, particularly in those with HBV-DNA <1000 IU/mL at week 48. In seven patients who did not achieve HBV-DNA negativity with ETV, noncompliance was reported in three patients, while another four patients responded to salvage therapy with either addition of or switching to TDF. It should be noted that there were some differences in the baseline characteristics of patients between our study and that of Zoutendjiket et al. Apart from our experience representing the largest series thus far, our patient population only had Asians, infected with HBV genotype B/C, and the majority (86%) were HBeAg positive whereas the majority of patients in the Zoutendjiket et al. study were non-Asians (72%), infected with HBV genotype D (48%) and A (21%), and HBeAg negative (57%). The current available data, including our study, are relatively small, uncontrolled and retrospective. Therefore, a prospective controlled study is needed to evaluate the best management strategy for patients with suboptimal response to ETV, while we also address the mechanisms for such an unfavourable clinical course.
In conclusion, suboptimal response to ETV is rare (approximately 3%). TDF monotherapy is a safe and very effective option for patients with suboptimal response to ETV.
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发表于 2012-3-21 21:23
