Abstract and Introduction
HBV resistance is the main limitation of long-term therapy with oral HBV polymerase inhibitors, which represent the most common approach in the treatment of chronic hepatitis B. The complete suppression of HBV replication minimises the risk of resistance and therefore close monitoring with sensitive HBV DNA determinations at least every 6 months is required. Lamivudine monotherapy has the highest risk of selecting resistant mutations compared with other anti-HBV agents and is not currently considered as an optimal first-line treatment. Adefovir has a similar profile but less potency than the other nucleotide analog, tenofovir, whereas telbivudine selects for lamivudine resistance mutants and therefore its place is currently unclear. Entecavir and possibly tenofovir are the two most potent anti-HBV agents with the best resistance profile in nucleo(s)tide-naive patients, while tenofovir represents the optimal treatment for patients with lamivudine resistance. Combination of two agents without cross-resistance should be used in any patient with HBV resistance.
Chronic HBV infection is a global public health problem representing an important cause of morbidity and mortality worldwide. Although universal HBV vaccination in infancy has decreased the incidence of new chronic HBV infections, there are still many patients with chronic hepatitis B (CHB) who are at high risk for complications of this disease if left untreated. It is estimated that up to 400 million people are chronically infected with HBV and that more than 500,000 people die every year owing to complications of HBV-related chronic liver disease.
Treatment for CHB has dramatically improved over the last 10 years mainly due to the development of safe and effective oral antiviral agents. Besides oral antiviral agents, IFN-α or pegylated-IFN-α (Peg-IFN-α) was, and still is, a first-line therapeutic approach for patients with CHB. In fact, standard IFN-α was the only available licensed therapeutic option for CHB until the late 1990s, while Peg-IFN-α was also approved for the treatment of CHB approximately 5 years ago (Peg-IFN-α-2a has been licensed for CHB worldwide, while Peg-IFN-α-2b has been licensed in some countries but not in Europe and the USA). Peg-IFN-α has now replaced practically standard IFN-α in the treatment of CHB. Although finite courses with Peg-IFN-α achieve sustained off-treatment responses in approximately 30% of hepatitis B e antigen (HBeAg)-positive and 20-25% of HBeAg-negative CHB patients, and have been shown to result in clearance of hepatitis B surface antigen (10-15% of total population after 5 years) and improve long-term outcomes of sustained responders, they are currently used in the minority of patients with CHB. Factors associated with the limited use of (Peg)-IFN-α therapy in CHB include the low probability of sustained response, parenteral administration, the relatively poor tolerability of IFN-α, and the frequent and potentially serious side effects in patients with advanced liver disease.
Oral antiviral agents represent the treatment approach used by the vast majority of CHB patients. Today, five oral antiviral agents have been licensed for the treatment of CHB: lamivudine, adefovir dipivoxil, entecavir, telbivudine and tenofovir disoproxil fumarate. They are all nucleos(t)ide analogs belonging to the same class of agents (HBV polymerase inhibitors). The initial development of oral anti-HBV agents was based on the knowledge from treatment of HIV, as there are similarities between the HBV and HIV replication cycles and there were clinical observations of clearance of HBV viremia during treatment of patients with HIV and HBV co-infection. Oral antiviral agents have potent anti-HBV activity, but they also have additional advantages. These include oral administration, excellent tolerance, the absence of serious side effects and negligible contraindications, offering therapeutic intervention in almost all CHB patients. Oral antivirals can be given even in patients with advanced liver disease (decompensated cirrhosis) who cannot be treated with (Peg)-IFN-α therapy.
One-year treatment with oral anti-HBV agents results in suppression of viral replication in the majority of CHB patients ( Table 1 ). Although effective and safe, the use of nucleos(t)ide analogs is not completely free of problems. The main limitation of these drugs is the progressively increasing rates of viral resistance due to selection of treatment-resistant HBV mutant strains. Since the probability of emergence of HBV-resistant strains increases with prolongation of therapy ( Table 1 ), the issue of viral resistance is strictly linked with the need for long-term duration of oral antiviral therapy, which is usually given for several years and perhaps indefinitely for some patients, particularly those with HBeAg-negative CHB. Of course, the rate of emergence of viral resistance is not the same for all anti-HBV agents, but resistance may develop under long-term treatment with any oral anti-HBV agent. Today, one of the most challenging issues in the management of CHB is the optimal use of the nucleos(t)ide analogs in order to achieve the best virologic responses, avoiding, as far as possible, the selection of resistant HBV mutants. This review comments on several issues related to HBV resistance under oral antiviral therapy, including definitions, incidence, monitoring and management.