A primary nonresponse to oral drugs against hepatitis B virus (HBV) is a generally accepted criterion for interrupting treatment. We investigated whether the concept of primary nonresponse suggested by current American (AASLD) and European (EASL) guidelines is appropriate for treatment with entecavir (ETV). The study included 1,254 treatment-naïve patients who had pretreatment HBV DNA levels of >2,000 IU/mL and received ETV 0.5 mg/day for over 6 months. “Primary nonresponse” was defined as a <2 log drop in HBV DNA after 6 months of therapy by AASLD and as a <1 log drop after 3 months by EASL. The cumulative probability of virological response (VR; HBV DNA of <15 IU/mL) was compared in patients with and without primary nonresponse. Median time to achieve VR was significantly shorter in primary responders by AASLD than nonresponders (12 versus 24 months; P = 0.004), but the cumulative probability of achieving a VR at 54 months was similar in the two groups (95.8% versus 100%). Time to achieve a VR and cumulative probability of VR over time did not differ between primary responders and nonresponders by EASL. On-treatment virological breakthrough occurred in 18 patients with a cumulative rate of 5.6% at 72 months. ETV resistance was detected in 13 of these 18 patients (72.2%), who were all classified as primary responder according to both guidelines. Conclusion: Long-term ETV therapy generally leads to a VR in treatment-naïve patients, although the time to achieve it is delayed in primary nonresponders. The current recommendation to change therapy in primary nonresponders needs to be modified to reflect drug differences in antiviral potency and resistance risk. (Hepatology 2014;59:1303-1310)
The presence of hepatitis B e antigen (HBeAg) is a well-established factor linked to progression of hepatitis B virus (HBV)-related liver disease. In addition, a large community-based cohort study in Taiwan has revealed that chronic elevation of hepatitis B viral replication carries increased risk of liver cirrhosis, hepatocellular carcinoma (HCC), and associated liver-related mortality.[1-3] The ultimate goal of treatment of chronic hepatitis B (CHB) is to suppress active viral replication and so minimize liver damage. Therefore, it is particularly important to achieve durable viral suppression, defined as reduction of serum HBV DNA to undetectable levels, especially after nucleoside/nucleotide analog (NA) therapy.[4-6]
Current guidelines on the management of CHB depend in part on the timepoints of the on-therapy measurements. They also depend on the extent of the decrease in HBV DNA level stipulated in the standardized definitions of categories of interim virological response (VR) to antiviral for deciding on an adaptation of treatment.[7-9] Given the substantial evidence that early on-treatment HBV DNA responses can strongly predict long-term virological outcomes, modification of the therapeutic regimen at early times is widely recommended not only for primary nonresponders but also for partial virological responders. However, the publications supporting this strategy are mostly based on data for less potent NAs such as lamivudine and telbivudine.[7, 9-14] Indeed, long-term therapy with newer and more potent antivirals (i.e., entecavir [ETV] and tenofovir [TDF]) can lead to virological remission in the vast majority of CHB patients, regardless of basal HBV DNA levels and HBeAg status.[15-17] A recent ETV study has suggested that, in contrast to the traditional guidelines, treatment adjustment is not essential even when patients have a partial VR at week 48, especially if their viral load at week 48 is low.
Given this situation, the aim of this study of a large single-center cohort of NA-naïve CHB patients treated with ETV monotherapy was to assess whether the definitions of primary nonresponses used to guide the CHB treatment algorithm suggested by the current universal guidelines are optimal or need to be refined on the basis of newer data.
The principle goals of treatment of CHB with oral NA are primarily to ensure sustained suppression of HBV virological activity as measured by quantification of HBV DNA, to alleviate hepatic inflammation, and to prevent progression to cirrhosis, HCC, and decompensated liver disease requiring liver transplantation. Successful treatment would thus decrease mortality.[1-6] We found that prolonged ETV monotherapy led to a VR in the vast majority of CHB patients, even in those that were HBeAg-positive, although the time to achieve a VR was clearly longer in patients not showing a primary response at 6 months as defined by AASLD criteria. Fortunately, the latter made up only 1.28% (16 patients) of the overall cohort. However, primary response at 3 months based on EASL did not predict long-term on-treatment virological outcomes. In our series, only 13 patients (1.0%) experienced virological breakthrough linked to the development of drug resistance during ETV treatment, and, moreover, none of these patients had a primary nonresponse to ETV. Interestingly, none of the 17 patients (1.4%) who developed HCC during ongoing treatment were primary nonresponders, or developed ETV resistance.
Given that early viral kinetic responses may be predictive of better outcomes and a reduced risk of viral resistance, primary on-treatment nonresponse or treatment failure is an indication for a change in therapy according to current evidence-based practice guidelines including the roadmap concept, providing compliance has been good. However, these guidelines are based on data from studies of less potent drugs with a higher risk of antiviral resistance, and which vary in terms of monitoring strategy.[7, 9-14] Although monotherapy with ETV or TDF is generally considered the initial choice of NA therapy for CHB, very little data are available about on-treatment management and, in particular, the applicability of the roadmap concept to CHB patients receiving this efficient drug. Hence, it seemed desirable to reappraise the current criteria for primary VR.
A multicenter European study from Zoutendijk et al. suggested that in the great majority of patients with CHB, HBV DNA is reduced to undetectable levels after prolonged (3-year) treatment with ETV even in those with partial VR, defined as a reduction in HBV DNA of >1 log but presence of HBV DNA detectable by real-time PCR assay at 48 weeks of therapy. Thus, they recommended that ETV treatment should be continued in these patients, especially those who have a low viral load (<1,000 IU/mL) at week 48, rather than adapting the treatment as recommended by EASL. These observations were also confirmed in our single-center cohort of Asian ETV-treated patients. However, the Zoutendijk et al. report compared final inhibitory effects on viral replication with interim virological outcomes measured at a single timepoint (48 weeks), which is not long and corresponds to on-treatment “partial VR” by the definition of the EASL guidelines, rather than to initial “primary VR.”
In our cohort of NA-naive patients, median time to achieve a VR was significantly longer for patients with primary nonresponse to ETV at week 24 by AASLD, whereas there was no difference in the time to VR when results were evaluated at week 12 by EASL. Importantly, the cumulative probability of achieving a VR after 54 months was around 95% in both primary responders and nonresponders as defined at 24 weeks, despite the difference in the rate at which VR was achieved. In view of the positive correlation between inflammatory activity of hepatocytes and viral replication activity, the longer persistence of detectable HBV DNA in the primary nonresponders may lead to greater host tissue injury. However, it is important to emphasize that viral load was maintained at very low levels during most of the on-treatment time even in our primary nonresponders. It is also possible that the between-group difference in baseline viremic burden, which was independently predictive of a VR in our analysis, could have a biasing effect on the on-treatment virological kinetics, although primary response by AASLD was strongly associated with ultimate achievement of VR. It is interesting that, in contrast to the current view that CHB patients with primary treatment failure are at risk of developing genotypic resistance,[26-28] there were no primary nonresponders among the 13 patients who were subsequently found to harbor ETV-resistant mutants. This observation supports the conclusion that there is no need for early treatment adjustment in slow responders. Studies are needed to clarify the long-term effects of the rate at which VR is achieved, and to investigate the benefit of early switching to TDF in patients who do not respond primarily to ETV. In addition, the effect of heterogeneity of genetic backgrounds on responses to treatment, especially slow responses, should be studied.
It has been shown that HBV suppression induced by antiviral therapy can reduce the risk of HCC.[29, 30] In our ETV-treated series, the 5-year cumulative HCC incidence rate was 2.5%, which was about average compared with data from recent long-term ETV studies, although initial host and virus factors differed between the studies.[15, 30, 31] For example, the most recently published Japanese study by Hosaka et al. reported that the cumulative HCC incidences were 3.7% and 13.7% at year 5 in the matched ETV-treated and control groups, respectively, and this difference was statistically significant. Because there were no primary nonresponders among our subset of patients diagnosed with HCC, we believe it would not be appropriate to individualize surveillance strategies for HCC based on the presence or absence of early on-treatment VR following ETV.
In terms of the on-treatment outcomes of the noncompliant patients excluded from the study, we found that although primary responses by AASLD, though not by EASL, were less frequent than in the final eligible compliant patients—probably due to poor adherence mainly in the first year of ETV treatment—optimal viral suppression was ultimately achieved in most of the cases. Note that this observation strongly supports our main conclusion from the patients finally recruited to the study. Interestingly, ETV-resistance mutations were never detected in the patients considered noncompliant, as was also observed in a previous smaller study. These surprising outcomes are presumably the result of the intensive educational interventions on medication adherence by clinicians in response to poor patient compliance as well, perhaps, as of the high anti-HBV potency of ETV per se.
An important limitation of this study is that our data were confined to ETV, and thus it remains to be established whether the current guidelines are clinically applicable to CHB patients initially receiving TDF, the other current first-line NA.
In conclusion, our validation analysis demonstrates that CHB patients with primary nonresponses at 6 months after the initiation of ETV treatment display a slower rate of reduction of viremia, but the vast majority of them finally become negative for HBV DNA in line with the primary responders. Also, a primary nonresponse to ETV is not associated with the selection of resistance mutations. Careful consideration is needed before modifying antiviral therapy in CHB patients with early suboptimal virological responses to ETV.