Evolution of Viral Load and Genome Sequence in a Clinical Trial of Tenofovir/Emtricitabine

Evolution of Viral Load and Genome Sequence in a Clinical Trial of Tenofovir/Emtricitabine Combination Versus Tenofovir Monotherapy for Patients with Previous Adefovir Dipivoxil Failure

EASL
44th Annual Meeting of the
European Association for the Study of the Liver
April 22 - 26, 2009
Copenhagen, Denmark
Reported by Jules Levin

F. Lavocat1, C. Pichoud1, P. Deny1, K. Borroto-Esoda2, J. Sorbel2, F. Rousseau2, D. Durantel1, F. Zoulim1 1U871, INSERM, Lyon, France; 2Gilead Sciences, Durham, USA

OBJECTIVE
In patients with ADV failure, it is therefore important to determine the potential benefit of a combination therapy over a switch strategy in patients with HBV DNA greater than 1000 copies/mL on ADV

The aim of the present study is to compare viral kinetics and polymerase gene resistance mutation evolution during antiviral therapy with TDF or TDF + emtricitabine (FTC) in patients with HBV DNA greater than 1000 copies/mL on ADV

AUTHOR CONCLUSIONS
InnoLiPA is significantly more sensitive to detect resistance mutations than population sequencing

Evolution of viral load was not different whether patients received combination or monotherapy

Baseline resistance patterns were not associated with type of response. A rapid response to < 400 copies/mL was correlated with low baseline viral load (p<0.05)

At Week 48, ADV-R and LAM-R mutations were found to persist by LiPA in two and one patient, respectively

17 patients have been selected for clonal analysis. These patients have been chosen for their different type of response, treatment regimen and baseline mutations

The viral quasi-species study and longer follow-up of these patients are ongoing to better understand viral kinetics and fitness during combination therapy and to evaluate the potential for cross resistance

INTRODUCTION
· Hepatitis B virus (HBV) is responsible for nearly 350 million chronic infections worldwide. More than 1 million people die each year following complication of the disease (cirrhosis or hepatocellular carcinoma) · Two types of therapies are approved for treatment of chronic hepatitis B: - Immunomodulation using interferon alpha. Only one third of patients respond to this treatment and inconvenient side effects are observed
- Inhibition of viral polymerase using nucleos(t)ide analogues. However, prolonged treatment with most nucelos(t)ide analogues results in emergence of resistant virus harboring mutations within the HBV polymerase gene associated with resistance to therapy

BACKGROUND
· Tenofovir disoproxyl fumarate (TDF) is a nucleotide analogue recently approved for HBV treatment. Currently, no resistance mutation has been described for TDF but adefovir dipivoxil (ADV) resistance mutations may confer some level of cross-resistance to TDF in vitro
· Combination therapy represents an emerging strategy for treating chronic HBV infection, although its added benefit is debated

METHODS

105 patients with chronic hepatitis B and refractory to ADV therapy were randomized and treated in a controlled trial of TDF versus TDF + FTC

63 patients had also been exposed to lamivudine before the trial