viral resistance. Commercial tests to determine the presence of antiviral drug resistance are also now available. Genotypic testing can also be performed through many reference laboratories using tests such as the INNOLiPA test in the US. This is a strip assay that identifies virus populations with drug-resistant mutations, and can measure down to levels as low as 5% of the overall population. However, mutations identified at the genotypic level—sequence changes—may not immediately result in viral breakthrough. Laboratory-based phenotypic methods of documenting resistance use cell cultures in research laboratories to establish the inhibitory concentration of the antiviral agent that is required to reduce viral load by ≥50% (IC50). Resistance is typically defined as a >10-fold increase in IC50 compared with that associated with a reference mutant. A <5-fold increase implies sensitivity to a given medication, and an increase in the 5- to 10-fold range suggests partial resistance.¹⁴ A rising HBV DNA level or lack of decline in DNA could signal resistance. Waiting until ALT levels begin to rise— indicating that resistance has been present for some time, and possibly signaling the presence of high levels of viral replication—may place patients at risk for progressive liver disease, flares, decompensation, or even urgent liver transplantation or death.

What Does a Practitioner Do Next to Manage Patients with Resistant Mutants? In patients with CHB who develop resistance to antiviral medications, there are two main strategies that can be employed:

• switching to an alternative agent—which should be avoided; or

• adding another antiviral drug—which is now the primary recommendation.

The majority of available data relates to patients with mutations that are associated with lamivudine-resistant CHB. Adefovir, entecavir, and tenofovir (currently not licensed for CHB) have been demonstrated to be effective against lamivudine-resistant mutants.^15-18 Telbivudine should not be added, and nor is a change to telbivudine recommended if mutations associated with lamivudine resistance are seen.

Adefovir—alone or in combination with lamivudine—results in a significant reduction in viral load, with a median change in baseline HBV DNA levels after 48 weeks of therapy of –4.04 and –3.59 log10 copies/ml, respectively, compared with no change in HBV DNA measurements in patients continuing lamivudine monotherapy.¹⁵ In patients with lamivudine-resistant CHB who receive adefovir, switch therapy (which is not recommended) with lamivudine should be continued for at least three months to prevent flares from the re-emergence of wild type virus. These flares have been associated with decompensation in patients. Evidence is emerging to suggest that resistance to adefovir occurs more rapidly in patients with lamivudine resistance.¹³ Fung et al. reported that adefovir resistance occurred only in patients who were switched from lamivudine therapy. This suggests that, although the combination of lamivudine and adefovir in patients with lamivudine-resistant mutants may not produce a significant increase in viral suppression compared with adefovir monotherapy, it does decrease the likelihood of the development of adefovir resistance.

A recent study reported that commencing adefovir therapy in patients with mutations associated with lamivudine resistance and evidence of treatment failure (defined as confirmed POL mutation(s) and lack of suppression below HBV DNA 3–6 log10 copies/ml and normal ALT) was more effective than waiting for viral breakthrough (rebound) of viral resistance (defined as confirmed POL mutation(s) and viral rebound or HBV DNA >6 log10 copies/ml and elevated ALT).¹¹ In HBeAg-negative patients, 100% of patients treated on evidence of genotypic resistance with POL mutations and who had HBV DNA levels <2,000 copies/ml after two years of subsequent adefovir therapy compared to 78% of those patients treated following the development of with high levels of virus and increase serum levels of ALT. These data support early and immediate intervention in patients with resistance.