Service d’hépatologie et de gastroentérologie, hospices civils de Lyon, Hôtel-Dieu, 69002 Lyon, France, Inserm U871, 69003 Lyon, France, Université Lyon-I, IFR62 Lyon-Est, 69008 Lyon, France
Treatment of chronic hepatitis B is based on the use of pegylated interferon (IFN-PEG) or nucleos(t)idic analogues and monotherapy is usually favored for most patients when initiating therapy. Entecavir and tenofovir are potent HBV inhibitors and exhibit a high barrier to resistance, which allows their use as first-line monotherapy. However, long-term treatment with the other nucleos(t)idic analogues leads to high-rates of resistance and in that case, an appropriate rescue therapy based on adding-on a second drug without cross-resistance is an efficient strategy. It is well known that a slow decline in HBV DNA and partial virological response are associated with resistance, indicating that patients with detectable HBV DNA 24 weeks after starting lamivudine or telbivudine or 48 weeks after starting adefovir should have their treatment changed. The relevance of de novo combination therapy to prevent resistance appearance has to be confirmed in long-term studies. However, it can eventually be recommended in patients whose liver function could not tolerate virological rebound and exacerbation of the disease, and should be evaluated in patients with a high-risk of developing resistance, i.e. those with a high baseline viral load and those with a long duration of infection prior to initiating therapy.