HBV ANTIVIRAL RESISTANCE

The goals of hepatitis B treatment are to eliminate or permanently suppress viral replication, normalize serum ALT levels and improve liver histology thereby reducing the risk of disease progression in patients chronically infected with Hepatitis B. In recent years the treatment of chronic hepatitis has greatly improved with the development of new therapeutic options. To date, two immunomodulators, interferon alpha and pegylated interferon and five nucleos(t)ide analogues (NA), lamivudine, adefovir, entecavir, telbivudine and tenofovir (not all countries), are all approved therapies for HBV. While the use of NAs rapidly suppress HBV replication, their long term efficacy is limited by the development of viral resistance.

Antiviral therapy with NA while effective does not completely inhibit the replication of the virus. As a consequence almost inevitably drug resistant HBV emerges. To date the primary resistance mutations have been identified for four out of the five currently approved NA. The emergence of drug resistance presents a significant challenge to clinicians:

• Limited treatment options
• One class of agents with one viral target (the polymerase)
• Reported clinical outcomes of combination therapy limited
• High level of cross resistance within structural groups of compounds and reduced sensitivity across the different structural groups of compounds

Antiviral resistance:

Virological breakthrough is often associated with the selection of drug resistance and is defined as an increase in HBV DNA levels (greater than or equal to 1 x log10 IU/ml) in patients who initially responded to antiviral therapy (Locarnini 2004, Ant Therapy 9:679-693). Genotyping of clinical isolates is required to confirm the presence of drug resistant HBV. Genotypic resistance is often associated with;

• Increasing serum ALT levels (flares, clinical deterioration)
• Reduced HBeAg seroconversion
• Histological progression of liver disease
• Increased recurrence in patients who have undergone OLT
• Changes in HBsAg envelope antigenicity

How Resistance Develops:

Like HIV, HBV replicates via an error prone viral reverse transcriptase. The transcriptase lacks a proof reading function, which allows for viral mutations to occur spontaneously during viral replication. This results in a pool of viral quasispecies that coexist in different proportions depending on their relative replicative fitness. The dominant species at any one time is the "fittest" virus, capable of replicating in the presence of selection pressure. The probability of selecting HBV variants resistant to an antiviral agent is affected by:

• The diversity of the viral pool
• The mutation rate and viral load
• The replicative fitness of the virus
• The intensity of the selection pressure or potency of the drug
• The number of mutations required to confer resistance (often referred to as the genetic barrier to resistance, in other words, the more mutations needed to confer resistance the higher the genetic barrier of that agent to resistance)

Primary resistance Mutations:

Resistance to NA is usually attributable to mutations that affect the reverse transcriptase (rt) coding region of the viral polymerase gene and alter the enzymatic properties of its product. The reverse transcriptase contains 7 functional domains (A-G), mutations associated with drug resistance are located in domains A through to E. NA are classified into three main groups according to their chemical structure:

1. L-Nucleoside analogues – Lamividine (LMV), emtricitabane, telbivudine
   (L-dT,L-thymidine), torcitabine (L-deoxycytidine) and clevudine (L-FMAU).
2. Acyclic nucleoside phosphonates – adefovir (ADV) and tenofovir (TDF).
3. Deoxyguanosine analogues – entecavir (ETV) and abacavir.

Lamivudine (Epivir-HBV, 3TC):

• Potent inhibitor of HBV DNA replication, prolonged treatment reverses fibrosis and cirrhosis
• Associated with high rates of drug emergence, which occurs at a cumulative rate of about 14-20% per year
• Primary resistance mutations rtM204V/I (+/- rtL180M)

Adefovir (Hepsera):

• Associated with lower rates of drug emergence, 2% after 2 years on therapy
• Effective against lamivudine-resistant HBV mutants
• Suboptimal virological response observed in ~18-20% of patients, which may be attributable to:
• Altered adefovir metabolism
• The 10mg daily dose (30mg daily has been shown clinically to be more effective but is frequently associated with renal toxicity)
• Primary resistance mutations rt N236T +/- rtA181V/T

Entecavir (Baraclude):

• 100 fold more potent than LMV or ADV
• Associated with low rates of drug emergence in drug naïve patients, 0.8% over 4 years (high genetic barrier to resistance)
• Reduced susceptibility of ETV to lamivudine resistant HBV mutants in vitro
• Much higher rates of drug emergence in LMV experienced (refractory) patients, 32% over 3 years
• Effective against adefovir-resistant HBV mutants
• Primary resistance mutations rt L180 + rtM20V +/- rtT184G +/- rtS202I +/- rtM250V

Telbivudine (Tyzeka, L-dT):

• Slower rate of drug emergence than LMV, over 2 years, 21.6% in HBeAg positive patients and 8.6% in HBeAg negative patients
• Primary resistance mutations, rt M204V/I

Tenofovir (Viread, not yet approved for HBV in all countries):

• Very potent HBV antiviral (superior to ADV)
• Effective against LMV resistant HBV
• Partially effective against ADV resistant HBV
• Primary resistance mutations yet to be determined

Hepatitis B Drug Anitviral Resistance Presentation

Below is 6 videos containing Professor Stephen Locarnini's (PhD) presentation "Hepatitis B Drug Anitviral Resistance: Navigating the Way Forward". The presentation has been broken into 6 sections, and accompanying each section is a downloadable pdf containing slides from the corresponding video.

SECTION 1 – What is Antiviral Drug Resistance?

SECTION 2 – How does resistance occur?

SECTION 3 – Hep B and Antiviral Resistance

SECTION 4 – Antiviral Drug Resistance Pathways

SECTION 5 – Managing Antiviral Drug Resistance

SECTION 6 – Preventing Antiviral Drug Resistance