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Hepatology May 2011 early view ahead of print
Roeland Zoutendijk1, Jurrien G.P. Reijnders1, Ashley Brown2, Fabien Zoulim3, David Mutimer4, Katja Deterding5, Jorg Petersen6, Wolf Peter Hofmann7, Maria Buti8,Teresa Santantonio9, Florian van Bommel10, Pierre Pradat3, Ye Oo4, Marc Luetgehetmann11, Thomas Berg10, Bettina E. Hansen1, Heiner Wedemeyer5 and Harry L.A. Janssen1 for the VIRGIL Surveillance Study Group.
Entecavir (ETV) is a potent inhibitor of viral replication in nucleos(t)ide analogue (NA)-naïve chronic hepatitis B (CHB) patients. The aim of this study was to investigate the long term efficacy and safety of ETV in NA-naïve CHB patients, particularly in those with detectable HBV DNA after 48 weeks, in whom treatment adaptation is suggested by current guidelines. In a multi-center cohort study we investigated 333 CHB patients treated with entecavir monotherapy. The NA-naïve population consisted of 243 patients, while 90 were NA- experienced. Virological response (VR, HBV DNA <80 IU/mL) was achieved in 48%, 76% and 90% of HBeAg-positive and in 89%, 98% and 99% of HBeAg-negative NA-naïve patients at week 48, 96 and 144, respectively. Thirty-six of 175 (21%) NA-naïve patients with at least 48 weeks follow-up had a detectable load at week 48 (partial virological response, PVR).
Twenty-nine (81%) patients with PVR reached VR during prolonged ETV monotherapy and none of them developed ETV-resistance. Among 22 patients with HBV DNA <1000 IU/mL at week 48, VR was achieved in 21 (95%) patients, compared to eight (57%) of 14 patients with HBV DNA ≥1000 IU/mL. Continuous HBV DNA decline was observed in most patients without VR during follow-up and in three patients adherence was suboptimal according to the treating physician. ETV was safe and did not affect renal function or cause lactic acidosis.
Conclusion: ETV monotherapy can be continued in NA-naïve patients with a detectable HBV DNA at week 48, particularly in those with a low viral load at week 48, as long-term ETV leads to a virological response in the vast majority of patients.
The current multicenter study showed that ETV is effective up to three years in NA-naïve patients, irrespective of having a virological response at week 48. The vast majority of NA- naïve patients with a PVR achieved undetectable HBV DNA through prolonged therapy without treatment adaptation. Genotypic resistance to ETV was not detected in any of the patients with a PVR at week 48. We showed that ETV is a safe antiviral drug with a good renal tolerance and minimal side effects. Persistent viral replication and the development of resistance during treatment with NA for CHB have been associated with an adverse treatment outcome.(8, 11) Therefore, EASL guidelines suggest treatment adaptation in patients with a PVR to prevent treatment failure and the development of resistance.(9) PVR is defined as a decline of >1 log IU/mL in HBV DNA but failure to achieve undetectable HBV DNA levels at week 48 in patients treated with continuous ETV monotherapy.
In our cohort of NA-naïve patients treated with ETV, 36 patients failed to achieve a VR at week 48. Among these patients with a PVR, 81% achieved a VR without treatment adaptation through 15 additional months of therapy. Cumulated probability of achieving VR beyond week 48 was higher for patients with HBV DNA <1000 IU/mL at week 48. Importantly, despite two patients experiencing a virological breakthrough, no resistance was detected in these NA-naïve patients. This is in accordance with the ETV phase III trial in which, albeit with incomplete follow-up, a substantial number of patients achieved a response beyond the first year of treatment, whilst genotypic resistance remained rare through 5 years of continuous monotherapy.(4, 12-13) Our findings are in contrast with previous studies on LdT/LAM and ADV in which persistent viral replication at week 24 and week 48 of therapy was identified as a predictor of the emergence of subsequent viral resistance.(8, 10) This highlights that treatment paradigms based on data from studies investigating agents with a low barrier to resistance cannot be translated to newer and more potent drugs as ETV and TDF.
Nevertheless, not all ETV-treated patients with a PVR achieved VR through prolonged treatment. As we, after thorough examination, determined non-compliance in three (43%) of these seven patients, this explains in our opinion primarily the inability to achieve HBV DNA undetectability. The problem of non-adherence is supported by a previous study suggesting partial response to ADV is most likely due to non-compliance and host pharmacological factors.(14) One of seven patients without a VR experienced a virological breakthrough and treatment was adapted by the treating physician. However, it is important to note that six (86%) of seven patients who failed to achieve a VR during follow-up still had a declining load at end of follow-up, which suggests that achieving a VR can probably be reached in the majority of cases. Patients with a PVR could therefore be considered 'slow responders' instead of partial responders. Taken together, our study shows that continuing ETV appears safe and effective in patients with detectable HBV DNA at week 48, especially in patients with a lower viral load at week 48, of whom 95% achieved VR.
Decreased sensitivity to ETV for LAM-refractory patients was soon known after introduction of this agent.(5, 15) Our study confirms these results as the antiviral efficacy of ETV is seriously diminished in these patients, even after correction for possible confounders as high baseline HBV DNA and HBeAg-positivity. Moreover, our study underlines that even after resistance testing at baseline; the absence of L AM-associated mutations does not guarantee a susceptible virus during ETV treatment. This suggests that if there is a suspected history of LAM-resistance, TDF containing regimens should be preferred instead of ETV monotherapy as LAM-resistance strains remain susceptible to TDF monotherapy.(16)
Consistent with in vitro data, our study showed that antiviral efficacy of ETV treatment was not influenced by prior exposure or resistance to ADV.(17-21) Until now only small studies or studies with a relatively short follow-up have confirmed the in vitro efficacy of ETV in ADV- experienced or ADV-resistant patients in real life practice.(6, 22-24) Our findings are of particular interest because both ETV and TDF can thus be used as salvage therapy for ADV-experienced patients.(9, 25) Data from the large phase III trials with a selected population showed that entecavir has few side effects in patients with compensated liver disease.(2-3) However, a recent report indicates that patients with decompensated cirrhosis are at risk for developing lactic acidosis.(26) We showed that ETV is safe during prolonged therapy in this heterogeneous cohort, even in the presence of cirrhosis. Moreover, we proved that ETV does not affect renal function, which might be a concern during TDF therapy.(27)
Limitations of our study are the observational design and the heterogeneous group of patients, yet we used Cox's regression to correct for confounders as treatment duration, HBV DNA, HBeAg status and previous LAM-resistance. Nevertheless, this heterogeneous population is also representative for clinical practice, and makes it possible to compare different groups of (NA-experienced) patients within one study.
In conclusion, in contrast to what is suggested in recently published EASL guidelines on the management of chronic hepatitis B, adjustment of ETV monotherapy in NA-naïve patients with a PVR at week 48 is not necessary. We demonstrated that continuous therapy beyond week 48 is safe and effective, and results in VR in the vast majority of patients, particularly in those with HBV DNA <1000 IU/mL at week 48. Furthermore, genotypic resistance to ETV was not observed in this subset of NA-naïve patients. For both NA-naïve and NA- experienced patients, ETV proved to have a favorable safety profile.
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