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Endpoints of Nucleos(t)ide Analogue Therapy
Maintenance of undetectable HBV DNA levels is an important on-treatment goal in nucleos(t)ide analogue–treated patients because a persistently detectable HBV DNA level during treatment is a major risk factor for the development of virologic breakthrough (a rise of HBV DNA ≥ 1 log above the nadir) and antiviral resistance.[130-132] The ultimate goal of therapy would be HBsAg seroclearance, as it is associated with the lowest risk of disease progression and HCC development, but this is infrequently achieved. Thus, the AASLD guidelines recognize that for HBeAg-positive patients receiving nucleos(t)ide analogue therapy, HBeAg seroconversion is an alternative endpoint, and treatment may be discontinued in patients who have achieved this endpoint and complete ≥ 12 months of consolidation therapy (the period of treatment after HBeAg seroconversion) after the appearance of anti-HBe (Table 9). Discontinuation of treatment after nucleos(t)ide analogue–induced HBeAg seroconversion is, however, associated with a high probability of posttreatment relapse (23% to 67%)[133-138] Continuation until HBsAg clearance is, therefore, a prudent alternative. Based on concerns about decompensation and death, the AASLD suggests continuing treatment indefinitely in patients with cirrhosis unless there is a strong reason to discontinue.
Similarly, discontinuing nucleos(t)ide analogue treatment in patients with HBeAg-negative chronic HBV infection will cause virologic relapse, defined as detectable HBV DNA after achieving a virologic response, in most patients.[139,140] For some patients, this posttreatment HBV DNA flare could result in an activation of the immune response resulting in viral clearance and HBsAg loss, but at the risk of severe hepatitis flares.[141,142] The safety of such a strategy is currently under investigation and is not recommended outside of clinical studies at this time. Therefore, the AASLD recommends continuing treatment indefinitely in patients with HBeAg-negative immune-active chronic HBV (Table 9). The guidance panel notes that discontinuing treatment in noncirrhotic patients who experience HBsAg loss may be considered; emerging evidence suggests the excellent durability of this approach, although further confirmation will be required.
Table 9. Duration and Endpoints of Therapy for Chronic HBV Infection[3,4]
Monitoring Patient Response to Nucleos(t)ide Analogues
Currently approved nucleos(t)ide analogues can adequately suppress HBV DNA levels, normalize ALT levels, and improve liver histology,[27,144] but their antiviral efficacy is markedly reduced in patients who develop drug-resistant HBV variants, resulting in virologic breakthrough, hepatitis flares, and a reduction in clinical benefits. Averting emergence of viral resistance is therefore essential to successful antiviral therapy with nucleos(t)ide analogues.
Persistent viral replication during antiviral therapy (measured by HBV DNA levels) is a major risk factor for the subsequent development of antiviral resistance.[74,84,130,146] Therefore, HBV DNA levels should be monitored every 3-4 months with a sensitive assay (limit of detection, 10 IU/mL) during the first year of treatment with nucleos(t)ide analogues according to the EASL. This interval can thereafter be extended to every 6-12 months. The AASLD guidelines recommend monitoring every 3 months until HBV DNA is undetectable and every 3-6 months after that. The APASL recommend monitoring HBV DNA at Month 3 and 6 and then at regular intervals, depending on the genetic barrier to resistance of the nucleos(t)ide analogues used: every 3-6 months for agents with low-genetic barrier (ie, lamivudine, adefovir, telbivudine) or every 6 months for agents with high-genetic barrier (ie, entecavir, tenofovir DF).
Current European guidelines recommend treatment modification in patients with detectable HBV DNA levels after a predefined duration of treatment.[4,130,147] The EASL guidelines have attempted to classify response patterns to nucleos(t)ide analogues and to advise treatment modification in suboptimal responders to prevent the development of resistance (Figure 4):
Figure 4. Patterns of response to nucleos(t)ide analogues.
According to guidelines, patients with a suboptimal response to nucleos(t)ide analogues at the predefined time points are eligible for treatment modification. Although there is an abundance of evidence for the advantages of treatment modification in patients with persistent viremia during therapy with lamivudine, telbivudine, and adefovir, such evidence is currently lacking for entecavir, tenofovir DF, and tenofovir AF. It is unclear whether treatment modification will improve results for nonresponders or partial responders to these latter treatments. In fact, therapy can probably be prolonged safely in partial responders to entecavir because treatment-naive patients treated with entecavir showed very low risk of resistance after 2-3 years of treatment, even in those with detectable HBV DNA.[37,148,149] In one study, partial responders to entecavir with HBV DNA < 1000 IU/mL at Week 48 of treatment were very likely to achieve undetectable HBV DNA during prolonged therapy; indeed 81% of patients achieved this endpoint. Similarly, a considerable number of patients continued to achieve undetectable HBV DNA through Years 2 and 3 of therapy in the entecavir and tenofovir DF registration trials and investigator-initiated cohort studies.[34,37,46,47] Prolongation of therapy, as opposed to treatment modification, therefore may be justified, for example in patients with a high HBV DNA at baseline or slow responders who may require additional months of therapy to achieve undetectable levels of HBV DNA.[47,130,150-152] Accordingly, the EASL practice guidelines suggest that patients with declining serum HBV DNA at 48 weeks of therapy may continue therapy with the same agent: entecavir, tenofovir DF, or tenofovir AF. If HBV DNA decline plateaus, a switch to one of the other 2 options is suggested or a combination approach of entecavir with either tenofovir DF or tenofovir AF.
The AASLD guidelines recommend continuing monotherapy with entecavir, tenofovir DF, or tenofovir AF regardless of ALT, in patients with persistent low-level viremia (ie, < 2000 IU/mL), defined as a plateau in the decline of HBV DNA and/or failure to achieve undetectable HBV DNA level after 96 weeks of therapy.
Adherence to Nucleos(t)ide Analogues. Nucleos(t)ide analogue therapy for chronic hepatitis B is often lifelong, and therefore, adherence to therapy is an important factor for success. One study showed that nearly 40% of virologic breakthroughs on therapy were not related to drug resistance, and thus, suboptimal adherence can be suspected. Another study showed that within a 16-week follow-up period, adequate adherence was observed in only 70% of patients and adherence was even lower among younger patients. Therefore, in patients with virologic breakthrough on therapy, it is important to check for medication compliance and confirm antiviral resistance with genotypic testing. An accurate assessment of the cause of virologic breakthrough is important to avoid unnecessary changes in the treatment regimen.
Management of Nucleos(t)ide Analogue–Experienced Patients and Patients With Antiviral Resistance
Emergence of viral resistance to nucleos(t)ide analogue therapy is the result of a 3-way interplay among HBV, the drug’s antiviral potency and resistance barrier, and host (immune) factors. The barrier to resistance varies significantly across the different nucleos(t)ide analogues and depends on the number of mutations in the viral genome that are required to confer resistance. Drugs with a low or intermediate barrier to resistance (lamivudine, adefovir, and telbivudine) require only a single or a few mutations in the viral genome for resistance to occur, whereas entecavir requires several mutations.[39,48] Tenofovir DF also exhibits a very high barrier to resistance.[48,155] Preliminary data from 2 phase III noninferiority trials also showed a lack of resistance to tenofovir AF time,[64,65] which is expected to exhibit a similarly high, and potentially even higher, barrier to resistance as tenofovir DF over time.
It is important to note that the viral mutations that arise during treatment are archived and may be selected for again when another treatment course is initiated. Therefore, resistance testing, using line-probe assays or direct sequencing, is important in treatment-experienced patients, although resistance mutations that are present only as minority species may not be detected.[39,158] Due to the high risk of cross-resistance among the different nucleos(t)ide analogues, the appropriate second agent(s) must be carefully selected for patients who are treatment experienced or who have confirmed resistance to 1 or more nucleos(t)ide analogue. Table 10 lists commonly encountered mutations associated with HBV antiviral resistance and their susceptibilities to the respective nucleos(t)ide analogue.
Table 10. Commonly Encountered Mutations and Susceptibility to Nucleos(t)ide Analogues
Table 11 lists possible options for treatment modification in patients who fail to respond to nucleos(t)ide analogues.[3,4,39]
Table 11. Options for Treatment Modification in the Case of a Suboptimal Response Based on Known Data on Cross-Resistance
Managing Lamivudine Resistance. Available guidelines from the AASLD and the EASL  suggest that either adding tenofovir DF, tenofovir AF, or emtricitabine/tenofovir DF (alternative) or switching to tenofovir DF or tenofovir AF[3,4] are the most appropriate choices for managing lamivudine resistance (Table 11). One trial comparing tenofovir DF alone vs in combination with emtricitabine in patients with lamivudine resistance demonstrated comparable efficacy, suggesting no decreased benefit with using tenofovir DF alone. These findings were confirmed during prolonged follow-up through 240 weeks. In 2013, the FDA approved an expanded indication for tenofovir DF for use in treatment experienced patients with documented resistance to lamivudine.
In lamivudine-treated patients without documented resistance, switching to entecavir at the higher 1.0 mg/day dose may be a feasible option.[36,37,160] In a study of 286 patients with detectable HBV DNA while receiving lamivudine who were randomized to receive entecavir 1.0 mg/day vs lamivudine 100 mg/day, compared with lamivudine-treated patients, entecavir-treated patients achieved significantly higher rates of histologic (28% vs 55%, respectively), virologic (1% vs 21%, respectively), and biochemical responses (23% vs 75%, respectively). However, in patients with lamivudine resistance, the efficacy of entecavir is markedly reduced and the risk of entecavir resistance is high, reaching more than 40% after 5 years of entecavir. Of importance, the efficacy of entecavir is also reduced in patients who have a history of lamivudine resistance, even in the absence of lamivudine resistance mutations at baseline. Given that information on previous lamivudine treatment failure is not always available, a switch to tenofovir DF may also be appropriate. Indeed, one study showed that 92% of 13 patients with lamivudine-resistant mutations who were switched to tenofovir DF achieved HBV DNA < 400 copies/mL at Week 48 of treatment.
The combination of entecavir and tenofovir DF may also be effective in the lamivudine-experienced population. Indeed, a study of entecavir plus tenofovir DF in patients with multidrug resistance showed that 51 out of 57 patients achieved undetectable HBV DNA in a median of 6 months of therapy.
The addition of adefovir to lamivudine monotherapy is also effective in many patients.[163-166] Indeed, add-on adefovir therapy in liver transplantation recipients was associated with HBV DNA reductions of 3-4 log10 copies/mL, which was sustained throughout the course of treatment. In addition, ALT levels normalized in 76% of pre–liver transplantation patients and 49% of post–liver transplantation patients.
Managing Adefovir Resistance. Adefovir-resistant mutants appear to be susceptible to entecavir, lamivudine, telbivudine, and tenofovir DF, although some have greater efficacy than others depending on the specific mutation(s). Indeed, entecavir, lamivudine, and telbivudine have all shown to be active in vitro against HBV variants with the N236T mutation frequently observed with adefovir therapy, whereas tenofovir DF has shown reduced efficacy against variants with this mutation. Conversely, tenofovir DF appears to be more active in vitro against the A181V/T mutation than lamivudine or telbivudine.[167,168] In vivo data have further shown reduced clinical efficacy of tenofovir DF in patients with adefovir resistance.[47,169,170] One study showed that patients with adefovir resistance mutations were significantly less likely to achieve HBV DNA < 400 copies/mL while receiving tenofovir DF vs those without adefovir resistance (P < .001). Therefore, for patients with adefovir resistance, current guidelines from the AASLD recommend either adding entecavir or switching to entecavir, tenofovir DF, or tenofovir AF (Table 11). Guidelines from the EASL recommend switching to entecavir, tenofovir DF, or tenofovir AF if the patient is lamivudine naive or switching to tenofovir DF or tenofovir AF if the patient is lamivudine resistant. Furthermore, if HBV DNA plateaus, adding or switching to entecavir is recommended.
Studies in clinical practice have shown high rates of virologic response in adefovir-resistant patients who switched to entecavir.[36,37,171] Indeed, one study showed that, of 8 patients with adefovir resistance who switched to entecavir monotherapy, all achieved HBV DNA < 100 IU/mL and 7 out of 8 achieved a biochemical response, defined as ALT < 40 U/L after 12 months of treatment. The combination of entecavir and tenofovir DF may also be effective in the adefovir-experienced population on the basis of data in multidrug-resistant HBV mentioned in the preceding section on lamivudine resistance.
Managing Telbivudine Resistance. In patients who have failed previous telbivudine treatment, adding or switching to tenofovir DF or tenofovir AF is recommended by current guidelines from the AASLD (Table 11). Similarly, the EASL recommends switching to tenofovir DF or tenofovir AF.
Managing Entecavir and Tenofovir Resistance. Resistance rates to entecavir are very low in the treatment-naive population; likewise, resistance to tenofovir DF has not been documented so far. Generally, most of the cases of persistent viremia during both entecavir or tenofovir DF will be due to suboptimal adherence. However, resistance testing remains indicated in entecavir-treated patients with persistent viremia when adherence to treatment is established.
In a multicenter, open-label phase IV study, 90 patients with documented entecavir resistance and detectable HBV DNA were randomized to either tenofovir DF alone (300 mg/day) or tenofovir DF plus entecavir (1 mg/day). Most patients were HBeAg positive (89%), and the median HBV DNA level at baseline was 4.02 log10 IU/mL. At Week 48, undetectable HBV DNA (< 15 IU/mL) was achieved in 71% and 73% (P > .99), respectively. There are no randomized trials that have evaluated the optimal strategy in those with persistent viremia during tenofovir DF therapy.
Current guidelines from the AASLD recommend adding tenofovir DF, tenofovir AF, or emtricitabine/tenofovir DF (alternative option) or switching to tenofovir DF or tenofovir AF for entecavir resistance. For patients with tenofovir DF or tenofovir AF resistance, addition of or a switch to entecavir is recommended. Finally, for patients with multidrug resistance, the AASLD includes options of switching to tenofovir DF or tenofovir AF or adding tenofovir DF or tenofovir AF plus entecavir (Table 11).  The AASLD guidelines note that out to 5 years of follow-up, efficacy is similar between add-on and switch approaches. Despite this, in the setting of drug resistance, switching is currently the preferred strategy except in the case of multidrug resistance.
The current guidelines from the EASL recommend switching to tenofovir DF or tenofovir AF for entecavir resistance; for tenofovir DF or tenofovir AF resistance, adding entecavir is recommended for lamivudine-resistant patients whereas switching to entecavir is recommended for lamivudine-sensitive patients (Table 11).[4,39]
Although guidance exists for the management of tenofovir resistance, it should be noted that such resistance is not clinically observed. Compliance should always be double-checked.