The goal of antiviral therapy for chronic hepatitis B (HBV) with oral nucleoside or nucleotide analogues is to ensure sustained suppression of HBV virologic activity as measured by quantitation of HBV DNA and ultimately, to prevent cirrhosis, hepatic failure, and hepatocellular cancer[1,2]. Unfortunately, prolonged therapy with some of these agents can result in the emergence of antiviral resistance. The development of resistance depends on a number of variables: pre-treatment HBV DNA levels, rapidity of viral suppression (often correlated with potency of agent), degree of genetic barrier to resistance of agent (threshold probability the virus will mutate under selective pressure from the drug), duration of treatment, and prior exposure to oral antiviral therapy[3]. Among the nucleoside analogue agents used to treat chronic HBV, different barriers to genetic resistance exist (Figure 1) and different rates of resistance have been reported to occur during treatment[1,4]. In this discussion, we will address the approach to patients with HBV who develop resistance to nucleoside analogues; HBV resistance to interferon and peginterferon preparations is not known to occur and will not be addressed.

Resistance Terminology

The AASLD guidelines provide the following terms related to antiviral resistance to nucleoside analogue treatment (Figure 2)[1].

Virologic breakthrough: a greater than 1 log10 (10-fold) rise in serum HBV DNA above nadir viral load in a patient who achieved initial viral suppression (during continued treatment).

Viral rebound: an increase in HBV DNA to greater than 20,000 IU/ml (or an increase above the pretreatment level) in a patient who attained an initial virologic response (during continued treatment).

Biochemical breakthrough: is characterized by a rise in serum ALT above the upper limit of normal after the patient achieves ALT normalization (during continued treatment).

Genotypic resistance: refers to specific DNA mutations known (based on in vitro studies) to confer resistance to a nucleoside antiviral agent.

Phenotypic resistance: refers to decreased in vitro susceptibility (as shown by an increase in inhibitory concentrations) to a nucleoside antiviral agent.

Consequences of Antiviral Resistance

The development of drug resistance has important clinical implications. In a study of cirrhotic patients with chronic hepatitis B who were treated with lamivudine versus placebo, disease progression (as measured by a composite endpoint of death and end-stage liver disease complications) occurred in 13% of patients who subsequently developed resistance on lamivudine compared with only 5% patients who did not develop resistance[5]. This observation is consistent with the finding that HBV replication is a major risk factor for cirrhosis and hepatocellular carcinoma in HBV-infected patients older than 40 years of age[6]. Thus, development of resistance leads to poorly controlled HBV, which then (if not dealt with) leads to increased risk of cirrhosis and hepatocellular carcinoma. In addition, the development of resistance can impact future treatment with other nucleoside analogues.

Evaluation of Patients with Virologic Breakthrough

In general, a rise in the HBV DNA level (virologic breakthrough) is the first sign of viral resistance and it precedes any biochemical breakthrough or symptomatic flare in hepatitis by weeks to months (Figure 2)[1]. Initial virologic breakthrough usually consists of low-level viremia (because the resistant HBV mutants have decreased replication fitness), but with continued treatment, compensatory mutations develop that can restore replication fitness and result in progressive increases in HBV DNA levels[4]. Patients with virologic breakthrough should first be questioned about their medication adherence. If a major problem with adherence is identified, we recommend making a strong effort to help the patient remedy this situation and then reassess HBV DNA levels 12 weeks later. If virologic breakthrough has occurred under optimal adherence, or if elevated HBV DNA levels persist after increased adherence efforts, then testing for HBV resistance should be performed to confirm antiviral resistance. Genotypic resistance assays are the most commonly used resistance test in this setting. Several commercial genotypic assays are available that use hybridization technology (such as the line probe assay) or direct PCR sequencing. Reliable performance of these assays requires a HBV DNA level greater than 200 IU/ml or 1000 copies/ml.

Resistance Profiles with Nucleoside Antiviral Agents

Genotypic testing can identify mutations in specific regions of the viral reverse transcriptase gene (Figure 3) that correlate with varying levels of resistance to specific agents (Figure 4)[2,4]. Treatment with lamivudine commonly leads to a mutation within the tyrosine-methionine-aspartate-aspartate (YMDD) motif in the reverse transcriptase region of the HBV polymerase gene. The primary mutation in this motif consists of the replacement of methionine by valine or isoleucine at the 204 codon, designated as M204V/I. The nomenclature M204V/I is preferred to YMDD because it conveys more accurate information regarding where the specific mutation has occurred. If the M204V/I mutation is present, lamivudine will not be effective. In addition, the M204V/I mutation results in varying degrees of cross-resistance to other nucleoside analogues (telbivudine, entecavir, and emtricitabine), which can reduce their efficacy. The development of the additional mutations S202I and M250V further decrease the efficacy of entecavir. The A181T mutation can confer resistance to lamivudine, adefovir, and tenofovir in vitro. The N236T mutation confers no resistance to lamivudine and entecavir but a 3 to 5-fold increased resistance to adefovir and tenofovir. To date, the significance of these mutations with respect to tenofovir is unclear as clinical resistance has not been described[2].

General Principles in the Management of Resistance

Therapy should be altered before a biochemical breakthrough occurs since biochemical breakthrough can result in a symptomatic hepatitis flare with marked ALT elevation (greater than 5 times upper limit of normal) and rarely hepatic decompensation[7,8]. Management of drug-resistant HBV most often consists of switching to a different agent, but, in some instances, involves adding a second agent[2] (Figure 5). The optimal approach in this situation remains unknown. It is important to consider the resistance profiles of the various agents (and potential cross-resistance) when making a choice in a patient who has developed resistance. Ideally, the next agent will have the greatest potency, least cross-resistance, and a high genetic barrier to resistance. Entecavir and tenofovir have the highest barrier to resistance among oral antiviral therapies to date, a result of the multiple mutations that need to occur before these antivirals lose their efficacy[4,9].

Management of Lamivudine Resistance

Treatment with lamivudine monotherapy is associated with a high rate of resistance, approaching 70% after 4 years of therapy[4,10]. The M204I/V mutation is the primary resistance mutation that develops in patients treated with lamivudine. Other mutations can develop with significant frequency, including the double mutations L180M + M204I and L180M + M204V; it appears the L180M mutation develops as a compensatory change after the M204I/V mutation. The preferred management strategy with lamivudine resistance consists of switching to an antiviral agent with a different resistance profile, typically tenofovir[2]. Treatment with tenofovir can suppress lamivudine-resistant HBV and available data suggest tenofovir is more effective than adefovir in this setting[11,12,13,14]. Adefovir can be added to lamivudine in those settings where tenofovir is not available or contraindicated. In HIV-coinfected patients in whom lamivudine remains active against HIV, the lamivudine can be continued or switched to emtricitabine and then given as the coformulated medication tenofovir-emtricitabine (Truvada). Entecavir at a higher dosage (1.0 mg) can provide clinical benefit to patients with lamivudine resistance[15]. Entecavir, however, is structurally similar to lamivudine and thus shares cross-resistance. As a result, lamivudine-resistant patients who receive entecavir 1.0 mg daily can develop entecavir resistance at a rate of 11 to 15% and 27 to 36% by 2 and 3 years, respectively[16,17]. When entecavir is used in lamivudine-resistant patients, the lamivudine should be discontinued[4]. Telbivudine generally does not have adequate activity against lamivudine-resistant HBV and thus should not be used to treat patients with lamivudine resistance.

Management of Telbivudine Resistance

Telbivudine is associated with a moderate rate of resistance when used as monotherapy, but at a lower rate than with lamivudine treatment[18]. Similar to lamivudine, the rates increase substantially after the first year of therapy. The M204I mutation is the primary mutation identified with telbivudine resistance. Thus, telbivudine and lamivudine share a similar resistance profile and have high-level cross-resistance. For patients on telbivudine who develop a M204V/I mutation, the approach should, in general, be the same as outlined above for lamivudine resistance[2].

Management of Entecavir Resistance

In patients who have not previously received lamivudine therapy, development of resistance with entecavir therapy only rarely occurs[19]. In contrast, patients with prior lamivudine therapy and lamivudine resistance development resistance when treated with entecavir at a significant rate, even when the higher 1.0 mg/day dose of entecavir is used. It appears that entecavir resistance results from a "2-hit" mechanism, with the first hit involving selection of lamivudine-associated mutations and the second hit consisting of additional entecavir mutations that develop in these prior selected strains. Obvious virologic failure does not generally occur until the second set of mutations develop. The most common resistance patterns observed with entecavir are the quadruple mutation patterns: I169T + L180M + M204V + M250V or L180M + T184G + S202I + M204V[4,20]. Other resistance patterns have been identified, but occur less frequently. When full entecavir resistance occurs, adding tenofovir is recommended, but limited clinical data are available[2,21]. Adding adefovir is also an option, but usually only recommended if tenofovir is not available.

Management of Adefovir Resistance

The development of adefovir resistance is most often associated with the N236T and/or A181T/V mutations[4]. These mutations generate partial cross-resistance to tenofovir, but apparently do not cause resistance to entecavir. Isolates with the N236T show in vitro susceptibility to lamivudine whereas those with A181T/V show resistance. In patients who develop adefovir resistance, there are several options. One option is to switch to entecavir or tenofovir if the patient has not received prior lamivudine, with the entecavir switch preferred in those with high-level viremia[2]. For patients with prior lamivudine exposure, switching to tenofovir is preferred[22]. Tenofovir has a higher barrier to resistance and greater potency compared with adefovir.

Management of Tenofovir Resistance

Very little is known regarding HBV resistance to tenofovir and management of tenofovir-resistant isolates. In a large trial of tenofovir versus adefovir in patients with chronic HBV, after 48 weeks of treatment, none of the 426 tenofovir-treated patients developed mutations in the DNA polymerase region associated with decreased sensitivity to tenofovir[23]. After 3 years of therapy, none of the patients in the follow-up study developed resistance to tenofovir[24]. A few studies have reported the development of the mutations A194T combined with lamivudine mutations (L180M and M204V) in HBV-HIV coinfected patients on tenofovir[25,26]. Although this mutation, like the adefovir resistance mutations N236T and A181T/V, has been demonstrated to result in reduced susceptibility in vitro, the clinical impact of these mutations is not known. If resistance is suspected it is reasonable to add entecavir, telbivudine, lamivudine, or emtricitabine.

Management of Multidrug Resistance

In patients who have developed resistance to both lamivudine and adefovir, therapy should be switched to tenofovir-emtricitabine (Truvada) or tenofovir plus entecavir. If there is resistance to both lamivudine and entecavir, the therapy should be changed to tenofovir alone or tenofovir-emtricitabine (Truvada). In principle, it is important to switch to a nucleoside (or nucleotide) analogue from a different structural class whenever possible. Combination therapy with agents that have complementary cross-resistance profiles is preferred in this setting. If options are limited for oral antiviral therapy, peginterferon should be considered, keeping in mind the contraindications for peginterferon therapy.

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    Figure 1. Genetic Barrier to Resistance for Nucleoside Analogue Agents used to Treat HBV
    Figure 1
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    Figure 2. Timing and Manifestations of Antiviral Resistance

    This graphic illustrates HBV DNA and ALT levels in association with development of resistance to HBV therapy. The HBV DNA levels during treatment are represented with the light blue line and the ALT levels over time are shown by the dark blue line. As shown, genotypic resistance precedes virologic breakthrough, which precedes major virologic rebound. Increases in ALT levels occur relatively late in this process.

    This figure is modified from Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507-39. Reproduced with permission from John Wiley & Sons, Inc.

    Figure 2
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    Figure 3. HBV Polymerase Nucleoside Analogue Resistance Mutations

    The HBV polymerase is shown at the top of figure, with expanded reverse transcriptase region and baseline amino acids and position shown below. Reverse transcriptase gene mutations result in amino acid substitutions. Amino acid codon substitutions known to correspond with resistance to nucleoside analogue agents are shown.

    Figure 3
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    Figure 4. In vitro and in vivo Significance of Antiviral-Resistant Mutations

    This figure is modified from Lok AS, Zoulim F, Locarnini S, et al. Antiviral drug-resistant HBV: standardization of nomenclature and assays and recommendations for management. Hepatology. 2007;46:254-65. Reproduced with permission from John Wiley & Sons, Inc.

    Figure 4
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    Figure 5. Recommended Strategies for Treating Antiviral-Resistant HBV

    This figure is modifed from European Association For The Study Of The Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection. J Hepatol. 2012;57:167-85.

    Figure 5