Assessment of Current Criteria for Primary Nonresponse in Chronic Hepatitis B Patients Receiving Entecavir Therapy

A primary nonresponse to oral drugs against hepatitis B virus (HBV) is a generally accepted criterion for interrupting treatment. We investigated whether the concept of primary nonresponse suggested by current American (AASLD) and European (EASL) guidelines is appropriate for treatment with entecavir (ETV). The study included 1,254 treatment-naive patients who had pretreatment HBV DNA levels of >2,000 IU/mL and received ETV 0.5 mg/day for over 6 months. Primary nonresponse was defined as a <2 log drop in HBV DNA after 6 months of therapy by AASLD and as a <1 log drop after 3 months by EASL. The cumulative probability of virological response (VR; HBV DNA of <15 IU/mL) was compared in patients with and without primary nonresponse. Median time to achieve VR was significantly shorter in primary responders by AASLD than nonresponders (12 versus 24 months; P = 0.004), but the cumulative probability of achieving a VR at 54 months was similar in the two groups (95.8% versus 100%). Time to achieve a VR and cumulative probability of VR over time did not differ between primary responders and nonresponders by EASL. On-treatment virological breakthrough occurred in 18 patients with a cumulative rate of 5.6% at 72 months. ETV resistance was detected in 13 of these 18 patients (72.2%), who were all classified as primary responder according to both guidelines. Conclusion: Long-term ETV therapy generally leads to a VR in treatment-naive patients, although the time to achieve it is delayed in primary nonresponders. The current recommendation to change therapy in primary nonresponders needs to be modified to reflect drug differences in antiviral potency and resistance risk. (Hepatology 2014;59:1303-1310)