This highlights the fact that the deepest level of viral suppression is obtained with the most potent agent in the group, but additive suppression and synergy are not obtained. Providing further support to this fact, the number of patients with HBV DNA levels <200 copies/ml was similar in both groups—41% in the lamivudine cohort and 39% in the combination group. Most importantly, patients receiving combination therapy were less likely to develop YMDD mutations after 52 weeks of therapy (20% compared with 2% of the combination group). Large, randomized, controlled studies are needed to define the use of this combination in clinical practice.

Confounding results were reported in a one-year trial of telbivudine alone or in combination with lamivudine.8 Telbivudine monotherapy produced suppression of viral replication to <200 copies/ml in 61% of patients compared with 41% who received combination therapy, and normalization of alanine aminotransferase (ALT) in 86% of those receiving telbivudine alone compared with 78% of the combination therapy group. Consequently, combination therapy offered no additional benefits over monotherapy and may have resulted in less deep suppression of HBV DNA, possibly due to competition for intracellular phosphate pools or competition of binding at the polymerase sites.

In patients with advanced liver disease—e.g. decompensated cirrhosis— combination therapy may be beneficial as the development of resistance in this group of patients can result in further decompensation and, in some cases, death.13 Entecavir as a single agent in treatment-naïve individuals should be useful, as there has been no resistance reported to date in this group of patients. Newer agents may offer the opportunity for combination therapy with improved efficacy and low rates of treatmentemergent resistance.

How Does a Clinician Identify Patients with Resistance?

The practitioner must divide failure of antiviral therapy into two groups: primary or secondary failure. Primary antiviral treatment failure is the failure of a drug to achieve a ≥1 log decrease of serum HBV DNA after three months of treatment.9 Secondary antiviral treatment failure occurs after an initial antiviral effect (≥1 log decrease in serum HBV DNA) and is defined as a confirmed rebound (breakthrough) of viral replication by ≥1 log compared with the lowest point (nadir) achieved with effective antiviral therapy in patients who continue to take the drug9 (see Figure 2). The virologic rebound should be confirmed by two consecutive laboratory measurements taken at least one month apart.

The main reasons for failure of antiviral therapy are:

• lack of potency;

• low viral dosing;

• poor adherence to therapy;

• pre-existing resistance mutations;

• reversion or lack of antiviral effect due to metabolic factors such as depletion of intracellular phosphate pools;

• selection of drug-resistant mutations of therapy; and

• noncompliance.

All patients commencing antiviral therapy should have quantitative HBV DNA measurements at baseline and three months after starting therapy.9 The purpose of this protocol is to identify individuals with response and primary treatment failure. This early time-point of three months is probably the best time to select and add an agent or change to an alternate therapy when the practitioner uses lamivudine. Subsequently, in patients with mild liver disease serum HBV DNA and ALT levels should be measured every three to six months during the first two years. With telvidune treatment, the decision to change or add a therapy should be taken at six months, as this time-point appears to be the best time to predict the development of resistance. Thereafter, if continuing monotherapy with on-going viral replication, the probability of treatment-emergent resistance increases. If continuing monotherapy, assessments of HBV DNA should be performed every three months. In patients who have advanced liver disease or cirrhosis—in whom the clinical consequences of resistance are more problematic—HBV DNA and ALT measurements in conjunction with careful clinical evaluation should be completed every three months from the outset of treatment, especially if monotherapy is being used.

Two laboratory methods are commonly used to assess the presence of antiviral resistant mutations—genotypic assays and phenotypic testing.14 Genotypic assaying involves direct DNA sequencing of the polymerase region for previously identified mutations associated with